5,7-DIAMINOPYRAZOLO [4,3-D] PYRIMIDINES WITH PDE-5 INHIBITING ACTIVITY

5,7-DIAMINOPYRAZOLO [4,3-D] PYRIMIDINES A EFFET INHIBITEUR PAR RAPPORT ALA PDE-5

English Abstract

This invention relates to compounds of formula (I).

French Abstract

La présente invention se rapporte à des composés répondant à la formule (I).

Claims

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CLAIMS:


1. A compound of formula (I)

Image
wherein
R1 is a cyclic group selected from R A, R B, R C and R D, each of which is
optionally
substituted with one or more R7 groups;

R2 is hydrogen or C1-C2 alkyl;

R3 and R4 are each independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or
C3-C10
cycloalkyl, each of which is optionally substituted with one or more R8
groups, or R E,
which is optionally substituted with one or more R9 groups, or hydrogen;

or -NR3R4 forms R F, which is optionally substituted with one or more R10
groups;
R5 is selected from -Y-CO2R15 and -Y-R16;

R6, which may be attached at N1 or N2, is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6
alkenyl or
C2-C6 alkynyl, each of which is optionally substituted by C1-C6 alkoxy, C1-C6
haloalkoxy or a cyclic group selected from R J, R K, R L and R M, or R6 is R
N, C3-C7
cycloalkyl or C3-C7 halocycloalkyl, each of which is optionally substituted by
C1-C6
alkoxy or C1-C6 haloalkoxy, or R6 is hydrogen;



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R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10
cycloalkyl,
C1-C10 halocycloalkyl, phenyl, OR12, OC(O)R12, NO2, NR12R13, NR12C(O)R13,
NR12CO2R14, C(O)R12, CO2R12, CONR12R13 or CN;

R8 is halo, phenyl, C1-C6 alkoxyphenyl, OR12, OC(O)R12, NO2, NR12R13,
NR12C(O)R13,
NR12CO2R14, C(O)R12, CO2R12, CONR12R13, CN, C3-C6 cycloalkyl, R G or R H, the
last two
of which are optionally substituted with one or more R9 groups;

R9 is C1-C6 alkyl, C1-C6 haloalkyl or CO2R12;

R10 is halo, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC(O)R12,
NO2,
NR12R13, NR12C(O)R13, NR12CO2R14, C(O)R12, CO2R13, CONR12R13, CN, oxo, C1-C6
alkyl
or C1-C6 haloalkyl, the last two of which are optionally substituted by R11;

R11 is phenyl, NR12R13 or NR12CO2R14;

R12 and R13 are each independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;
R14 is C1-C6 alkyl or C1-C6 haloalkyl;

R15 is hydrogen or C1-C6 alkyl optionally substituted with one or more groups
selected
from halo, OH, C1-C6 alkyloxy, NH2, NH(C1-C6alkyl) and N(C1-C6 alkyl)2;

R16 is a carboxylic acid isostere selected from tetrazol-5-yl, 5-
trifluoromethyl-1,2,4-
triazol-3-yl, 5-(methylsulfonyl)-1,2,4-triazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-
oxadiazol-3-
yl, -SO2NHR17 and -CONHR18;

R17 is selected from C1-C6 alkyl, phenyl, -CO-(C1-C6 alkyl) and -CO-phenyl;
R18 is selected from -SO2-(C1-C6 alkyl) and -SO2-phenyl;



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R A and R J are each independently a C3-C10 cycloalkyl or C3-C10 cycloalkenyl
group,
each of which may be either monocyclic or, when there are an appropriate
number
of ring atoms, polycyclic and which may be fused to either

(a) a monocyclic aromatic ring selected from a benzene ring and a 5- or
6-membered heteroaromatic ring containing up to three heteroatoms selected
from
nitrogen, oxygen and sulphur, or
(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur;

R B and R K are each independently a phenyl or naphthyl group, each of which
may be
fused to
(a) a C5-C7 cycloalkyl or C5-C7 cycloalkenyl ring,
(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur, or
(c) a 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur;

R C, R L and R N are each independently a monocyclic or, when there are an
appropriate number of ring atoms, polycyclic saturated or partly unsaturated
ring
system containing between 3 and 10 ring atoms, of which at least one is a
heteroatom selected from nitrogen, oxygen and sulphur, which ring may be fused
to
a C5-C7 cycloalkyl or C5-C7 cycloalkenyl group or a monocyclic aromatic ring
selected
from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up
to
three heteroatoms selected from nitrogen, oxygen and sulphur;

R D and R M are each independently a 5- or 6-membered heteroaromatic ring
containing up to three heteroatoms independently selected from nitrogen,
oxygen
and sulphur, which ring may further be fused to

(a) a second 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur;
(b) C5-C7 cycloalkyl or C5-C7 cycloalkenyl ring;



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(c) a 5-, 6- or 7-membered heteroalicyclic ring
containing up to three heteroatoms selected from nitrogen,
oxygen and sulphur; or

(d) a benzene ring;

R E, R F and R G are each independently a monocyclic or, when
there are an appropriate number of ring atoms, polycyclic
saturated ring system containing between 3 and 10 ring
atoms, of which at least one is a heteroatom selected from
nitrogen, oxygen and sulphur;

R H is a 5- or 6-membered heteroaromatic ring containing up to
three heteroatoms independently selected from nitrogen,
oxygen and sulphur; and

Y is a covalent bond, -CH2-O-CH2-, C1-C6 alkylenyl or C3-C7
cycloalkylenyl;

a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer.

2. A compound according to claim 1, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R1 is R A, which is
optionally substituted with one or more R7 groups; and

R A is a C3-C10 cycloalkyl group, which may be either
monocyclic or, when there are an appropriate number of ring
atoms, polycyclic, which may be fused to either

(a) a monocyclic aromatic ring selected from a
benzene ring and a 5- or 6-membered heteroaromatic ring
containing up to three heteroatoms selected from nitrogen,
oxygen and sulphur, or



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(b) a 5-, 6- or 7-membered heteroalicyclic ring

containing up to three heteroatoms selected from nitrogen,
oxygen and sulphur.

3. A compound according to claim 2, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R A is a monocyclic C3-C8
cycloalkyl group.

4. A compound according to claim 3, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R A is a monocyclic C5-C7
cycloalkyl group.

5. A compound according to claim 4, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R A is cyclopentyl or
cyclohexyl.

6. A compound according to claim 1, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R1 is R B, which is
optionally substituted with one or more R7 groups.

7. A compound according to claim 6, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R B is phenyl.

8. A compound according to claim 1, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R1 is R C, which is
optionally substituted with one or more R7 groups.

9. A compound according to claim 8, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R C is a monocyclic
saturated or partly unsaturated ring system containing



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between 3 and 8 ring atoms, of which at least one is a
heteroatom selected from nitrogen, oxygen and sulphur.
10. A compound according to claim 9, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R C is a monocyclic
saturated or partly unsaturated ring system containing
between 5 and 7 ring atoms, of which at least one is a
heteroatom selected from nitrogen, oxygen and sulphur.

11. A compound according to claim 10, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R C is a monocyclic
saturated ring system containing between 5 and 7 ring atoms,
of which at least one is a heteroatom selected from
nitrogen, oxygen and sulphur.

12. A compound according to claim 1, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R1 is R D, which is
optionally substituted with one or more R7 groups.

13. A compound according to claim 12, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R D is a 5- or 6-membered
heteroaromatic ring containing up to three heteroatoms

independently selected from nitrogen, oxygen and sulphur.
14. A compound according to claim 13, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R D is a 5-membered
heteroaromatic ring containing a heteroatom selected from
nitrogen, oxygen and sulphur and optionally up to two
further nitrogen atoms in the ring, or a 6-membered
heteroaromatic ring including 1, 2 or 3 nitrogen atoms.



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15. A compound according to claim 14, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R D is furanyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,
isothiazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl,
pyrimidyl or pyrazinyl.

16. A compound according to claim 15, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R D is pyrazolyl,
imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl,
pyridazinyl, pyrimidyl or pyrazinyl.

17. A compound according to any one of claims 1 to 16,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R7 is halo,
C1-C6 alkyl, C1-C6 haloalkyl, OR12 or CONR12R13.

18. A compound according to claim 17, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R7 is halo, C1-C3 alkyl,
C1-C3 alkoxy, hydroxy or CONH(C1-C3 alkyl).

19. A compound according to claim 18, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R7 is fluoro, methyl,
ethyl, hydroxy, methoxy, propoxy or CONHMe.

20. A compound according to any one of claims 1 to 19,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R2 is hydrogen
or methyl.

21. A compound according to claim 20, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R2 is hydrogen.



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22. A compound according to any one of claims 1 to 21,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R3 is hydrogen,
C1-C6 alkyl, which is optionally substituted with one or more
R8 which is optionally substituted with one or
a groups, or R E

more R9 groups; and wherein R E is a monocyclic or, when there
are an appropriate number of ring atoms, polycyclic
saturated ring system containing between 3 and 7 ring atoms,
of which at least one is a heteroatom selected from
nitrogen, oxygen and sulphur.

23. A compound according to claim 22, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R3 is hydrogen, C1-C4
alkyl, which is optionally substituted with one or more R8
groups, or R E, which is optionally substituted with one or
more R9 groups; and wherein R E is a monocyclic saturated ring
system containing between 3 and 7 ring atoms, of which at
least one is a heteroatom selected from nitrogen, oxygen and
sulphur.

24. A compound according to claim 23, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R3 is R E, which is
optionally substituted with one or more R9 groups and wherein
R E is a monocyclic saturated ring system containing between 3
and 7 ring atoms containing one nitrogen atom.

25. A compound according to claim 24, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R E is azetidinyl,
pyrrolidinyl or piperidinyl.

26. A compound according to claim 23, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R3 is C1-C4 alkyl, which



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is optionally substituted with one or more R8 groups and
wherein R8 is halo, phenyl, C1-C6 alkoxyphenyl, OR12, NR12R13
NR12CO2R14, CO2R12, CONR12R13, R G or R H, the last two of which
are optionally substituted with one or more R9 groups.

27. A compound according to claim 26, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R8 is hydroxy, methoxy,
methoxyphenyl, NH2, NHMe, NMe2, NHCO2t Bu, NMeCO2t Bu, CO2H,
CONHMe, R G or R H, the last two of which are optionally
substituted with one or more R9 groups.

28. A compound according to claim 27, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R8 is R G, which is
optionally substituted with one or more R9 groups and wherein
R G is a monocyclic saturated ring system containing between 3
and 7 ring atoms, of which at least one is a heteroatom
selected from nitrogen, oxygen and sulphur.

29. A compound according to claim 28, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R G is a monocyclic
saturated ring system containing between 3 and 7 ring atoms
containing one nitrogen atom and optionally one oxygen atom.
30. A compound according to claim 29, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R G is pyrrolidinyl,
piperidinyl or morpholinyl.

31. A compound according to claim 27, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R8 is R H, which is
optionally substituted with one or more R9 groups and wherein



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R H is a 5- or 6-membered heteroaromatic ring containing up to
two nitrogen atoms.

32. A compound according to claim 31, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R H is pyrazolyl.

33. A compound according to any one of claims 22

to 32, a tautomer thereof or a pharmaceutically acceptable
salt or solvate of said compound or tautomer, wherein R9 is
methyl or CO2tBu.

34. A compound according to claim 23, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R3 is hydrogen or C1-C4
alkyl, which is optionally substituted with one or more R8
groups, or R3 is azetidinyl, pyrrolidinyl or piperidinyl,
each of which is optionally substituted with one or more R9
groups, wherein

R8 is hydroxy, methoxy, methoxyphenyl, NH2, NHMe, NMe2,
NHCO2t Bu, NMeCO2t Bu, CO2H, CONHMe, pyrrolidinyl, piperidinyl,
morpholinyl or pyrazolyl, the last four of which are
optionally substituted with one or more R9 groups and wherein
R9 is methyl or CO2t Bu.

35. A compound according to any one of claims 1 to 34,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R4 is hydrogen,
C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl or C2-C6 alkynyl.
36. A compound according to claim 35, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R4 is hydrogen, C1-C6
alkyl or C1-C6 haloalkyl.



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37. A compound according to claim 36, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R4 is hydrogen, methyl or
ethyl.

38. A compound according to any one of claims 1 to 21,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein -NR3R4 forms
R F, which is optionally substituted with one or more R10
groups and wherein R F is a monocyclic or, when there are an
appropriate number of ring atoms, polycyclic saturated ring
system containing between 3 and 10 ring atoms containing at
least one nitrogen atom and optionally one other atom
selected from oxygen and sulphur.

39. A compound according to claim 38, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R F is a monocyclic or,
when there are an appropriate number of ring atoms,
polycyclic saturated ring system containing between 3 and 10
ring atoms containing one or two nitrogen atoms and
optionally one other atom selected from oxygen and sulphur.
40. A compound according to claim 39, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R F is selected from
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, 3-azabicyclo[3.1.0]hex-3-yl, homopiperazinyl,
2,5-diazabicyclo[4.3.0]non-2-yl, 3,8-diazabicyclo[3.2.1]oct-
3-yl, 3,8-diazabicyclo[3.2.1]oct-8-yl, 2,5-
diazabicyclo[2.2.1]hept-2-yl, 1,4-diazabicyclo[4.3.0]non-4-
yl and 1,4-diazabicyclo[3.2.2]non-4-yl.

41. A compound according to any one of claims 38

to 40, a tautomer thereof or a pharmaceutically acceptable
salt or solvate of said compound or tautomer, wherein R10 is



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halo, OR12, NR12R13, NR12CO2R14, CO2R13, oxo, C1-C6 alkyl or C1-C6
haloalkyl, the last two of which are optionally substituted
by R11.

42. A compound according to claim 41, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R10 is halo, methyl,
ethyl, isopropyl, hydroxy, methoxy, NH2, NHMe, NMe2, NHCO2t Bu,
CO2H, CO2t Bu, oxo, benzyl, -CH2NH2, -CH2NHMe, CH2NMe2 or

-CH2NMeCO2t Bu.

43. A compound according to any one of claims 1 to 42,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R5 is -Y-CO2R15.
44. A compound according to claim 43, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R15 is hydrogen or C1-C3
alkyl and Y is a covalent bond.

45. A compound according to any one of claims 1 to 42,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R5 is -Y-R16.
46. A compound according to claim 45, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R16 is -CONHR18, tetrazol-
5-yl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl and Y is a
covalent bond or a methylene group.

47. A compound according to any one of claims 1 to 46,
a tautomer thereof or a pharmaceutically acceptable salt or
solvate of said compound or tautomer, wherein R6 is
positioned on N1.

48. A compound according to any one of claims 1 to 47,
a tautomer thereof or a pharmaceutically acceptable salt or



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solvate of said compound or tautomer, wherein R6 is C1-C6
alkyl or C1-C6 haloalkyl, each of which is optionally
substituted by C1-C6 alkoxy, C1-C6 haloalkoxy or a cyclic
group selected from R J, R L and R M, or R6 is R N or hydrogen;
R J is a C3-C7 monocyclic cycloalkyl group;

R L and R N are each independently a monocyclic, saturated or
partly unsaturated ring system containing between 4 and 7
ring atoms, of which at least one is a heteroatom selected
from nitrogen, oxygen and sulphur; and

R M is a 5- or 6-membered heteroaromatic ring containing up to
three heteroatoms independently selected from nitrogen,
oxygen and sulphur.

49. A compound according to claim 48, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R6 is C1-C4 alkyl or C1-C4
haloalkyl, each of which is optionally substituted by C1-C4
alkoxy, C1-C4 haloalkoxy or a cyclic group selected from R J,
R L and R M, or R6 is R N or hydrogen;

R J is cyclopropyl or cyclobutyl;

R L and R N are each independently a monocyclic saturated ring
system containing either 5 or 6 ring atoms, of which at
least one is a heteroatom selected from nitrogen, oxygen and
sulphur; and

R M is a 5- or 6-membered heteroaromatic ring containing a
heteroatom selected from nitrogen, oxygen and sulphur.
50. A compound according to claim 49, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R6 is C1-C4 alkyl or C1-C4
haloalkyl, each of which is optionally substituted by C1-C4



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alkoxy or a cyclic group selected from R J, R L and R M, or R6 is
R N or hydrogen;

R J is cyclopropyl or cyclobutyl;

R L and R N are each independently a monocyclic saturated ring
system containing either 5 or 6 ring atoms containing one
heteroatom selected from nitrogen, oxygen and sulphur; and
R M is a 5- or 6-membered heteroaromatic ring containing one
nitrogen atom.

51. A compound according to claim 50, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R6 is C1-C4 alkyl or C1-C4
haloalkyl, each of which is optionally substituted by C1-C4
alkoxy, cyclopropyl, cyclobutyl, tetrahydrofuranyl,
tetrahydropyranyl or pyridinyl, or R6 is hydrogen or
tetrahydropyranyl.

52. A compound according to claim 51, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R6 is hydrogen, methyl,
ethyl, isopropyl, isobutyl, methoxyethyl, methoxypropyl,
ethoxyethyl, ethoxypropyl, propoxyethyl, 2,2,2-
trifluoroethyl, tetrahydrofuranylmethyl,
tetrahydropyranylmethyl, tetrahydropyranyl or
pyridinylmethyl.

53. A compound according to claim 1, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein

R3 is hydrogen, C1-C4 alkyl, which is optionally substituted
with one or more R8 groups, or R E, which is optionally
substituted with one or more R9 groups;



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R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

or -NR3R4 forms R F, which is optionally substituted with one
or more R10 groups;

R6 is C1-C4 alkyl or C1-C4 haloalkyl, each of which is
optionally substituted by C1-C4 alkoxy, C1-C4 haloalkoxy or a
cyclic group selected from R J, R L and R M, or R6 is R N or
hydrogen;

R A is a monocyclic C3-C8 cycloalkyl group;
R B is phenyl;

R C is a monocyclic saturated or partly unsaturated ring
system containing between 3 and 8 ring atoms, of which at
least one is a heteroatom selected from nitrogen, oxygen and
sulphur;

R D is a 5- or 6-membered heteroaromatic ring containing up to
three heteroatoms independently selected from nitrogen,
oxygen and sulphur;

R E is a monocyclic saturated ring system containing between 3
and 7 ring atoms, of which at least one is a heteroatom
selected from nitrogen, oxygen and sulphur;

R F is a monocyclic or, when there are an appropriate number
of ring atoms, polycyclic saturated ring system containing
between 3 and 10 ring atoms, of which at least one is a
heteroatom selected from nitrogen, oxygen and sulphur;

R J is cyclopropyl or cyclobutyl;

R L and R N are each independently a monocyclic saturated ring
system containing either 5 or 6 ring atoms, of which at
least one is a heteroatom selected from nitrogen, oxygen and
sulphur;



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R M is a 5- or 6-membered heteroaromatic ring containing a
heteroatom selected from nitrogen, oxygen and sulphur; and
Y is a covalent bond or C1-C6 alkylenyl.

54. A compound according to claim 53, a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
said compound or tautomer, wherein R1 is a cyclic group
selected from R A, R B, R C and R D, each of which is optionally
substituted with one or more R7 groups;

R7 is halo, C1-C6 alkyl, C1-C6 haloalkyl, OR12 or CONR12R13;
R8 is halo, phenyl, C1-C6 alkoxyphenyl, OR12, NR12R13,
12CO2R14, CO2R12, CONR12R13, R G or R H, the last two of which
are optionally substituted with one or more R9 groups;

R A is a monocyclic C5-C7 cycloalkyl group;
R B is phenyl;

R C is a monocyclic saturated ring system containing between 5
and 7 ring atoms, of which at least one is a heteroatom
selected from nitrogen, oxygen and sulphur;

R D is a 5-membered heteroaromatic ring containing a
heteroatom selected from nitrogen, oxygen and sulphur and
optionally up to two further nitrogen atoms in the ring or a
6-membered heteroaromatic ring including 1, 2 or 3 nitrogen
atoms;

R E is a monocyclic saturated ring system containing between 3
and 7 ring atoms containing one nitrogen atom;

R F is a monocyclic or, when there are an appropriate number
of ring atoms, polycyclic saturated ring system containing
between 3 and 10 ring atoms containing at least one nitrogen



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atom and optionally one other atom selected from oxygen and
sulphur;

R G is a monocyclic saturated ring system containing between 3
and 7 ring atoms, of which at least one is a heteroatom
selected from nitrogen, oxygen and sulphur;

R H is a 5- or 6-membered heteroaromatic ring containing up to
two nitrogen atoms; and

Y is a covalent bond or -CH2-.
55. A compound:

methyl 5-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2-
ethoxyethyl)-7-(4-methyl-pyridin-2-ylamino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carboxylate,
methyl 1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(6-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylate,

ethyl 1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylate,

2-(dimethylamino)ethyl 5-dimethylamino-1-(2-ethoxyethyl)-7-
(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylate,

1-(2-ethoxyethyl)-5-(N-methyl-N-propylamino)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-
1-(2-propoxy-ethyl)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,


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7-(4,6-dimethylpyridin-2-ylamino)-1-(2-ethoxyethyl)-5-(N-
isopropyl-N-methyl-amino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

5-(N-cyclobutyl-N-methylamino)-1-(2-ethoxyethyl)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

1-(2-ethoxyethyl)-5-isopropylamino-7-(4-methylpyridin-2-
ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(2-

methoxypyrimidin-4-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

3- [1- (2-ethoxyethyl) -5- (N-isopropyl-N-methylamino) -7- (4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-
2H-1,2,4-oxadiazol-5-one,

3- [1- (2-ethoxyethyl) -5- (N-ethyl-N-methylamino) -7- (4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-
2H-1,2,4-oxadiazol-5-one,

1-(2-ethoxyethyl)-7-(4-fluoro-3-methylphenylamino)-5-(N-
isopropyl-N-methylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-fluoro-3-
methylphenylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic
acid,

7-(3,4-dimethylphenylamino)-1-(2-ethoxyethyl)-5-(N-ethyl-N-
methylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
1-(2-(cyclopropylmethoxy)ethyl)-5-(N-isopropyl-N-

methylamino)-7-(4-methyl-pyridin-2-ylamino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,



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1-(2-(cyclopropylmethoxy)ethyl)-5-(N-ethyl-N-methylamino)-7-
(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

1-(2-isopropoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid,

N-[1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carbonyl]methanesulfonamide,

N-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carbonyl]methanesulfonamide,

N-[5-(Ethyl-methyl-amino)-1-[2-(3-fluoro-propoxy)-ethyl]-7-
(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carbonyl]-methanesulfonamide

N-[1-[2-(3-Fluoro-propoxy)-ethyl]-5-(isopropyl-methyl-
amino)-7-(4-methyl-pyridin-2-ylamino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide
N-[5-Diethylamino-1-[2-(3-fluoro-propoxy)-ethyl]-7-(4-
methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carbonyl]-methanesulfonamide

N-[5-Diethylamino-1-[2-(2,2-difluoro-ethoxy)-ethyl]-7-(4-
methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carbonyl]-methanesulfonamide


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N- [1- [2- (2, 2-Difluoro-ethoxy) -ethyl] -5- (ethyl-methyl-amino) -
7-(4-methyl-pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-
3-carbonyl]-methanesulfonamide, or

N- [1- [2- (2, 2-Difluoro-ethoxy) -ethyl] -5- (isopropyl-methyl-
amino)-7-(4-methyl-pyridin-2-ylamino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carbonyl]-methanesulfonamide,
or a tautomer thereof or a pharmaceutically acceptable salt
or solvate of said compound or tautomer.

56. The compound 1-(2-ethoxyethyl)-5-
(methyl(propyl)amino)-7-(4-methylpyridin-2-ylamino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid; a tautomer
thereof or a pharmaceutically acceptable salt or solvate of

the compound or tautomer.

57. The compound 3-(1-(2-ethoxyethyl)-5-
(ethyl(methyl)amino)-7-(4-methylpyridin-2-ylamino)-1H-
pyrazolo[4,3-d]pyrimidin-3-yl)-1,2,4-oxadiazo1-5(2H)-one; a
tautomer thereof or a pharmaceutically acceptable salt or
solvate of the compound or tautomer.

58. The compound 1-(2-ethoxyethyl)-7-(4-fluoro-3-
methylphenylamino)-5-(isopropyl(methyl)amino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid; a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
the compound or tautomer.

59. The compound 1-(2-ethoxyethyl)-5-(N-isopropyl-N-
methylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-
d]pyrimidine-3-carboxylic acid; a tautomer thereof or a
pharmaceutically acceptable salt or solvate of the compound
or tautomer.

60. The compound N-[1-(2-ethoxyethyl)-5-(N-isopropyl-
N-methylamino)-7-(4-methylpyridin-2-ylamino)-1H-


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pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide; a
tautomer thereof or a pharmaceutically acceptable salt or
solvate of the compound or tautomer.

61. The compound N-[1-(2-ethoxyethyl)-5-(N-ethyl-N-
methylamino)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-
d]pyrimidine-3-carbonyl]methanesulfonamide; a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
the compound or tautomer.

62. A pharmaceutical composition comprising a compound
as claimed in any one of claims 1 to 55, or a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
the compound or tautomer, and a pharmaceutically acceptable
diluent or carrier.

63. A pharmaceutical composition comprising the
compound 1- (2-ethoxyethyl) -5- (methyl (propyl) amino) -7- (4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid; a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer; and
a pharmaceutically acceptable diluent or carrier.

64. A pharmaceutical composition comprising the
compound 3- (1- (2-ethoxyethyl) -5- (ethyl (methyl) amino) -7- (4-
methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-
1,2,4-oxadiazol-5(2H)-one; a tautomer thereof or a
pharmaceutically acceptable salt or solvate of the compound
or tautomer; and a pharmaceutically acceptable diluent or
carrier.

65. A pharmaceutical composition comprising the
compound 1-(2-ethoxyethyl)-7-(4-fluoro-3-methylphenylamino)-
5-(isopropyl(methyl)amino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid; a tautomer thereof or a pharmaceutically


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acceptable salt or solvate of the compound or tautomer; and
a pharmaceutically acceptable diluent or carrier.

66. A pharmaceutical composition comprising the
compound 1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-
(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carboxylic acid; a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer; and
a pharmaceutically acceptable diluent or carrier.

67. A pharmaceutical composition comprising the
compound N-[1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-
7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-
3-carbonyl]methanesulfonamide; a tautomer thereof or a

pharmaceutically acceptable salt or solvate of the compound
or tautomer; and a pharmaceutically acceptable diluent or
carrier.

68. A pharmaceutical composition comprising the
compound N-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-
(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidine-3-
carbonyl]methanesulfonamide; a tautomer thereof or a
pharmaceutically acceptable salt or solvate of the compound
or tautomer; and a pharmaceutically acceptable diluent or
carrier.

69. A compound as claimed in any one of claims 1
to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
use as a medicament.

70. A compound as claimed in any one of claims 1
to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
use as a medicament for the treatment of a disease or


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condition where inhibition of PDE5 is known, or can be
shown, to produce a beneficial effect.

71. A compound as claimed in any one of claims 1
to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
use as a medicament for the treatment of a disease or
condition selected from hypertension, congestive heart
failure, angina, stroke, coronary artery disease, congestive
heart failure, conditions of reduced blood vessel patency,
peripheral vascular disease, atherosclerosis, nitrate-
induced tolerance, nitrate tolerance, diabetes, impaired
glucose tolerance, metabolic syndrome, obesity, sexual
dysfunction, premature labour, pre-eclampsia, dysmenorrhea,
polycystic ovary syndrome, benign prostatic hyperplasia,
bladder outlet obstruction, incontinence, chronic
obstructive pulmonary disease, acute respiratory failure,
bronchitis, chronic asthma, allergic asthma, allergic
rhinitis, gut motility disorders, Kawasaki's syndrome,
multiple sclerosis, Alzheimer's disease, psoriasis, skin
necrosis, scarring, fibrosis, pain, cancer, metastasis,
baldness, nutcracker oesophagus, anal fissure and
haemorrhoids.

72. A compound as claimed in any one of claims 1
to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer for
use as a medicament for the treatment of essential
hypertension, pulmonary hypertension, secondary
hypertension, isolated systolic hypertension, hypertension
associated with diabetes, hypertension associated with
atherosclerosis, renovascular hypertension; stable, unstable
or variant angina; post-percutaneous coronary angioplasty;
male erectile disorder, impotence, female sexual arousal
disorder, clitoral dysfunction, female hypoactive sexual


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desire disorder, female sexual pain disorder, female sexual
orgasmic dysfunction or sexual dysfunction due to spinal
cord injury; irritable bowel syndrome or neuropathic pain.
73. A compound as claimed in any one of claims 1

to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
use as a medicament for the treatment of pulmonary
hypertension.

74. A compound as claimed in any one of claims 1
to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
use as a medicament for the treatment of pain.

75. A compound as claimed in any one of claims 69
to 74, a tautomer thereof or a pharmaceutically acceptable
salt or solvate of said compound or tautomer, for use in
combination with pregabalin.

76. The pharmaceutical composition according to any
one of claims 62 to 68 for treatment of a disorder or
condition where inhibition of PDE5 is known, or can be
shown, to produce a beneficial effect, in a mammal.

77. The pharmaceutical composition according to any
one of claims 62 to 68 for the treatment of a disease or
condition selected from hypertension, congestive heart
failure, angina, stroke, coronary artery disease, congestive
heart failure, conditions of reduced blood vessel patency,
peripheral vascular disease, atherosclerosis, nitrate-
induced tolerance, nitrate tolerance, diabetes, impaired
glucose tolerance, metabolic syndrome, obesity, sexual
dysfunction, premature labour, pre-eclampsia, dysmenorrhea,
polycystic ovary syndrome, benign prostatic hyperplasia,
bladder outlet obstruction, incontinence, chronic


-281-
obstructive pulmonary disease, acute respiratory failure,
bronchitis, chronic asthma, allergic asthma, allergic
rhinitis, gut motility disorders, Kawasaki's syndrome,
multiple sclerosis, Alzheimer's disease, psoriasis, skin
necrosis, scarring, fibrosis, pain, cancer, metastasis,
baldness, nutcracker oesophagus, anal fissure and
haemorrhoids.

78. The pharmaceutical composition according to any
one of claims 62 to 68 for the treatment of essential
hypertension, pulmonary hypertension, secondary
hypertension, isolated systolic hypertension, hypertension
associated with diabetes, hypertension associated with
atherosclerosis, renovascular hypertension; stable, unstable
or variant angina; post-percutaneous coronary angioplasty;
male erectile disorder, impotence, female sexual arousal
disorder, clitoral dysfunction, female hypoactive sexual
desire disorder, female sexual pain disorder, female sexual
orgasmic dysfunction or sexual dysfunction due to spinal
cord injury; irritable bowel syndrome or neuropathic pain.
79. The pharmaceutical composition according to any
one of claims 62 to 68 for the treatment of pulmonary
hypertension.

80. The pharmaceutical composition according to any
one of claims 62 to 68 for the treatment of pain.

81. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, in
the preparation of a medicament for the treatment of a
disorder or condition where inhibition of PDE5 is known, or
can be shown, to produce a beneficial effect.


-282-
82. Use according to claim 81, wherein the disorder or
condition is selected from hypertension, congestive heart
failure, angina, stroke, coronary artery disease, congestive
heart failure, conditions of reduced blood vessel patency,
peripheral vascular disease, atherosclerosis, nitrate-
induced tolerance, nitrate tolerance, diabetes, impaired
glucose tolerance, metabolic syndrome, obesity, sexual
dysfunction, premature labour, pre-eclampsia, dysmenorrhea,
polycystic ovary syndrome, benign prostatic hyperplasia,
bladder outlet obstruction, incontinence, chronic
obstructive pulmonary disease, acute respiratory failure,
bronchitis, chronic asthma, allergic asthma, allergic
rhinitis, gut motility disorders, Kawasaki's syndrome,
multiple sclerosis, Alzheimer's disease, psoriasis, skin
necrosis, scarring, fibrosis, pain, cancer, metastasis,
baldness, nutcracker oesophagus, anal fissure and
haemorrhoids.

83. Use according to claim 82, wherein the disorder or
condition is essential hypertension, pulmonary hypertension,
secondary hypertension, isolated systolic hypertension,

hypertension associated with diabetes, hypertension
associated with atherosclerosis, renovascular hypertension;
stable, unstable or variant angina; post-percutaneous
coronary angioplasty; male erectile disorder, impotence,
female sexual arousal disorder, clitoral dysfunction, female
hypoactive sexual desire disorder, female sexual pain
disorder, female sexual orgasmic dysfunction or sexual
dysfunction due to spinal cord injury; irritable bowel
syndrome or neuropathic pain.

84. Use according to claim 82, wherein the disorder or
condition is hypertension.


-283-
85. Use according to claim 84, wherein the disorder or
condition is selected from essential hypertension, pulmonary
hypertension, secondary hypertension, isolated systolic
hypertension, hypertension associated with diabetes,
hypertension associated with atherosclerosis, and
renovascular hypertension.

86. Use according to claim 84, wherein the disorder or
condition is pulmonary hypertension.

87. Use according to claim 82, wherein the disorder or
condition is pain.

88. Use according to claim 82, wherein the disorder or
condition is diabetes.

89. A pharmaceutical composition comprising a compound
as claimed in any one of claims 1 to 61, or a tautomer
thereof or a pharmaceutically acceptable salt or solvate of
the compound or tautomer, and a second pharmaceutically
active agent selected from aspirin, angiotensin II receptor
antagonists, calcium channel blockers, beta-blockers,
CI10.27, CCR5 receptor antagonists, imidazolines, soluble
guanylate cyclase activators, antihypertensive agents,
diuretics, alpha adrenergic antagonists, ACE (angiotensin
converting enzyme) inhibitors, aldosterone receptor
antagonists, neutral endopeptidase inhibitors, antidiabetic
agents, cholesterol lowering agents, and alpha-2-delta
ligands.

90. The pharmaceutical composition according to
claim 89, wherein the second pharmaceutically active agent
is a beta-adrenergic receptor antagonist, a sulfonylurea, or
a glitazone.



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91. The pharmaceutical composition according to
claim 89, wherein the second pharmaceutically active agent
is pregabalin.

92. The pharmaceutical composition according to any
one of claims 89 to 91 for use in the treatment of a disease
or condition selected from hypertension, congestive heart
failure, angina, stroke, coronary artery disease, congestive
heart failure, conditions of reduced blood vessel patency,
peripheral vascular disease, atherosclerosis, nitrate-
induced tolerance, nitrate tolerance, diabetes, impaired
glucose tolerance, metabolic syndrome, obesity, sexual
dysfunction, premature labour, pre-eclampsia, dysmenorrhea,
polycystic ovary syndrome, benign prostatic hyperplasia,
bladder outlet obstruction, incontinence, chronic
obstructive pulmonary disease, acute respiratory failure,
bronchitis, chronic asthma, allergic asthma, allergic
rhinitis, gut motility disorders, Kawasaki's syndrome,
multiple sclerosis, Alzheimer's disease, psoriasis, skin
necrosis, scarring, fibrosis, pain, cancer, metastasis,
baldness, nutcracker oesophagus, anal fissure and
haemorrhoids.

93. The pharmaceutical composition according to any
one of claims 89 to 91 for use in the treatment of essential
hypertension, pulmonary hypertension, secondary
hypertension, isolated systolic hypertension, hypertension
associated with diabetes, hypertension associated with
atherosclerosis, renovascular hypertension; stable, unstable
or variant angina; post-percutaneous coronary angioplasty;
male erectile disorder, impotence, female sexual arousal
disorder, clitoral dysfunction, female hypoactive sexual
desire disorder, female sexual pain disorder, female sexual
orgasmic dysfunction or sexual dysfunction due to spinal
cord injury; irritable bowel syndrome or neuropathic pain.



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94. The pharmaceutical composition according to any
one of claims 89 to 91 for use in the treatment of pulmonary
hypertension.

95. The pharmaceutical composition according to any
one of claims 89 to 91 for use in the treatment of pain.
96. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, in
the preparation of a medicament combined with a second
pharmaceutically active agent selected from aspirin,
angiotensin II receptor antagonists, calcium channel
blockers, beta-blockers, CI1027, CCR5 receptor antagonists,
imidazolines, soluble guanylate cyclase activators,
antihypertensive agents, diuretics, alpha adrenergic
antagonists, ACE (angiotensin converting enzyme) inhibitors,
aldosterone receptor antagonists, neutral endopeptidase
inhibitors, antidiabetic agents, cholesterol lowering
agents, and alpha-2-delta ligands, for the treatment of a
disease or condition where inhibition of PDE5 is known, or
can be shown, to produce a beneficial effect.

97. Use according to claim 96, wherein the second
pharmaceutically active agent is a beta-adrenergic receptor
antagonist, a sulfonylurea, or a glitazone.

98. Use according to claim 96, wherein the second
pharmaceutically active agent is pregabalin.

99. Use according to claim 96, 97 or 98, wherein the
disease or condition is selected from hypertension,
congestive heart failure, angina, stroke, coronary artery
disease, congestive heart failure, conditions of reduced
blood vessel patency, peripheral vascular disease,
atherosclerosis, nitrate-induced tolerance, nitrate



-286-

tolerance, diabetes, impaired glucose tolerance, metabolic
syndrome, obesity, sexual dysfunction, premature labour,
pre-eclampsia, dysmenorrhea, polycystic ovary syndrome,
benign prostatic hyperplasia, bladder outlet obstruction,
incontinence, chronic obstructive pulmonary disease, acute
respiratory failure, bronchitis, chronic asthma, allergic
asthma, allergic rhinitis, gut motility disorders,
Kawasaki's syndrome, multiple sclerosis, Alzheimer's
disease, psoriasis, skin necrosis, scarring, fibrosis, pain,
cancer, metastasis, baldness, nutcracker oesophagus, anal
fissure and haemorrhoids.

100. Use according to claim 99, wherein the disease or
condition is essential hypertension, pulmonary hypertension,
secondary hypertension, isolated systolic hypertension,

hypertension associated with diabetes, hypertension
associated with atherosclerosis, renovascular hypertension;
stable, unstable or variant angina; post-percutaneous
coronary angioplasty; male erectile disorder, impotence,
female sexual arousal disorder, clitoral dysfunction, female
hypoactive sexual desire disorder, female sexual pain
disorder, female sexual orgasmic dysfunction or sexual
dysfunction due to spinal cord injury; irritable bowel
syndrome or neuropathic pain.

101. Use according to claim 99, wherein the disease or
condition is pain.

102. Use according to claim 100, wherein the disease or
condition is pulmonary hypertension.

103. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
the treatment of a disease or condition selected from
hypertension, congestive heart failure, angina, stroke,



-287-

coronary artery disease, congestive heart failure,
conditions of reduced blood vessel patency, peripheral
vascular disease, atherosclerosis, nitrate-induced
tolerance, nitrate tolerance, diabetes, impaired glucose
tolerance, metabolic syndrome, obesity, sexual dysfunction,
premature labour, pre-eclampsia, dysmenorrhea, polycystic
ovary syndrome, benign prostatic hyperplasia, bladder outlet
obstruction, incontinence, chronic obstructive pulmonary
disease, acute respiratory failure, bronchitis, chronic
asthma, allergic asthma, allergic rhinitis, gut motility
disorders, Kawasaki's syndrome, multiple sclerosis,
Alzheimer's disease, psoriasis, skin necrosis, scarring,
fibrosis, pain, cancer, metastasis, baldness, nutcracker
oesophagus, anal fissure and haemorrhoids.

104. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
the treatment of essential hypertension, pulmonary
hypertension, secondary hypertension, isolated systolic
hypertension, hypertension associated with diabetes,
hypertension associated with atherosclerosis, renovascular
hypertension; stable, unstable or variant angina; post-
percutaneous coronary angioplasty; male erectile disorder,
impotence, female sexual arousal disorder, clitoral
dysfunction, female hypoactive sexual desire disorder,
female sexual pain disorder, female sexual orgasmic
dysfunction or sexual dysfunction due to spinal cord injury;
irritable bowel syndrome or neuropathic pain.

105. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
the treatment of pulmonary hypertension.



-288-

106. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, for
the treatment of pain.

107. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, in
combination with pregabalin for the treatment of a disease
or condition selected from hypertension, congestive heart
failure, angina, stroke, coronary artery disease, congestive
heart failure, conditions of reduced blood vessel patency,
peripheral vascular disease, atherosclerosis, nitrate-
induced tolerance, nitrate tolerance, diabetes, impaired
glucose tolerance, metabolic syndrome, obesity, sexual
dysfunction, premature labour, pre-eclampsia, dysmenorrhea,
polycystic ovary syndrome, benign prostatic hyperplasia,
bladder outlet obstruction, incontinence, chronic
obstructive pulmonary disease, acute respiratory failure,
bronchitis, chronic asthma, allergic asthma, allergic
rhinitis, gut motility disorders, Kawasaki's syndrome,
multiple sclerosis, Alzheimer's disease, psoriasis, skin
necrosis, scarring, fibrosis, pain, cancer, metastasis,
baldness, nutcracker oesophagus, anal fissure and
haemorrhoids.

108. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, in
combination with pregabalin for the treatment of essential
hypertension, pulmonary hypertension, secondary

hypertension, isolated systolic hypertension, hypertension
associated with diabetes, hypertension associated with
atherosclerosis, renovascular hypertension; stable, unstable
or variant angina; post-percutaneous coronary angioplasty;



-289-

male erectile disorder, impotence, female sexual arousal
disorder, clitoral dysfunction, female hypoactive sexual
desire disorder, female sexual pain disorder, female sexual
orgasmic dysfunction or sexual dysfunction due to spinal
cord injury; irritable bowel syndrome or neuropathic pain.
109. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, in
combination with pregabalin for the treatment of pulmonary
hypertension.

110. Use of a compound as claimed in any one of

claims 1 to 61, or a tautomer thereof or a pharmaceutically
acceptable salt or solvate of the compound or tautomer, in
combination with pregabalin for the treatment of pain.

111. A compound of formula (III)
Image
wherein R1, R2, R6 and Y are are as defined in claim 1 and RA
is C1-C6 alkyl or benzyl.

112. A compound according to claim 111 of formula (IIID)



Image
113. A compound of formula (V)

Image
wherein R6 and Y are as defined in claim 1 and R A is C1-C6
alkyl or benzyl.

114. A compound according to claim 113 of formula (V B)
Image

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE I)E CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME DE _2

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des
Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

THIS IS VOLUME 1 OF 2

NOTE: For additional volumes please contact the Canadian Patent Office.


CA 02546987 2006-05-23
WO 2005/049616 PCT/IB2004/003747
-1-
5,7-DIAMINOPYRAZOLO `4,3-D!PYRIMIDINES WITH PDE-5 INHIBITING ACTIVITY

The present invention relates to a series of novel 5,7-diaminopyrazolo[4,3-d]
pyrimidines, which are cyclic guanylate monophosphate (cGMP)-specific
phosphodiesterase type 5 inhibitors (hereinafter referred to as PDE-5
inhibitors) that
are useful in the treatment of hypertension and other disorders, to processes
for
their preparation, intermediates used in their preparation, to compositions
containing
them and the uses of said compounds and compositions.

i) Hypertension
Blood pressure (BP) is defined by a number of haemodynamic parameters taken
either in isolation or in combination. Systolic blood pressure (SBP) is the
peak
arterial pressure attained as the heart contracts. Diastolic blood pressure is
the
minimum arterial pressure attained as the heart relaxes. The difference
between
the SBP and the DBP is defined as the pulse pressure (PP).

Hypertension, or elevated BP, has been defined as a SBP of at least 140mmHg
and/or a DBP of at least 90mmHg. By this definition, the prevalence of
hypertension in deveioped countries is about 20% of the adult population,
rising to
about 60-70% of those aged 60 or more, although a significant fraction of
these
hypertensive subjects have normal BP when this is measured in a non-clinical
setting. Some 60% of this older hypertensive population have isolated systolic
hypertension (ISH), i.e. they have an elevated SBP and a normal DBP.
Hypertension is associated with an increased risk of stroke, myocardial
infarction,
atrial fibrillation, heart failure, peripheral vascular disease and renal
impairment
(Fagard, RH; Am. J. Geriatric Cardiology 11(1), 23-28, 2002; Brown, MJ and
Haycock, S; Drugs 59(Suppl 2), 1-12, 2000).

The pathophysiology of hypertension is the subject of continuing debate. While
it is
generally agreed that hypertension is the result of an imbalance between
cardiac
output and peripheral vascular resistance, and that most hypertensive subjects
have


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abnormal cardiac output and increased peripheral resistance there is
uncertainty
which parameter changes first (Beevers, G et al.; BMJ 322, 912-916, 2001).
Despite the large number of drugs available in various pharmacological
categories,
including diuretics, alpha-adrenergic antagonists, beta-adrenergic
antagonists,
calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors and
angiotensin receptor antagonists, the need for an effective treatment of
hypertension
is still not satisfied.

ii) PDE5 inhibitors

Vascular endothelial cells secrete nitric oxide (NO). This acts on vascular
smooth
muscle cells and leads to the activation of guanylate cyclase and the
accumulation
of cyclic guanosine monophosphate (cGMP). The accumulation of cGMP causes
the muscles to relax and the blood vessels to dilate. This dilation reduces
vascular
resistance and so leads to a reduction in blood pressure.

The cGMP is inactivated by hydrolysis to guanosine 5'-monophosphate (GMP) by a
cGMP-specific phosphodiesterase. One important phosphodiesterase has been
identified as Phosphodiesterase type 5 (PDE5). Inhibitors of PDE5 decrease the
rate of hydrolysis of cGMP and so potentiate the actions of nitric oxide.
Inhibitors of PDE5 have been reported in several chemical classes, including:
pyrazolo[4,3-d]pyrimidin-7-ones (e.g. published international patent
applications WO
93/06104, WO 98/49166, WO 99/54333, WO 00/24745, WO 01/27112 and WO
01/27113); pyrazolo[3,4-d]pyrimidin-4-ones (e.g. published international
patent
application WO 93/07149); pyrazolo[4,3-d]pyrimidines (e.g. published
international
patent application WO 01/18004); quinazolin-4-ones (e.g. published
international
patent application WO 93/12095); pyrido[3,2-d]pyrimidin-4-ones (e.g. published
international patent application WO 94/05661); purin-6-ones (e.g. published
international patent application WO 94/00453); hexahydro-
pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-diones (e.g. published
international


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application WO 95/19978) and imidazo[5,1-fJ[1,2,4]triazin-ones (e.g. published
international application WO 99/24433).

Although they have been suggested as agents for the treatment of related
conditions
such as angina, PDE5 inhibitors have not yet been adopted as agents for the
treatment of hypertension. PDE5 inhibitors are known for the treatment of male
erectile dysfunction, e.g. sildenafil, tadalafil and vardenafil. There remains
a
demand for new PDE5 inhibitors, particularly with improved pharmacokinetic and
pharmacodynamic properties. The compounds provided herein are potent
inhibitors
of PDE5 that have improved selectivity in vitro and/or an extended half-life
in vivo.
WO 02/00660 and WO 01/18004 disclose pyrazolo[4,3-d]pyrimidines with a PDE-5
inhibiting effect, which can be used for treating disorders of the
cardiovascular
system.

According to a first aspect, the present invention provides compounds of
formula (I)
1 R 2
RN
I
R6 N N
%\ Ra
N N
R5 R4 ( I )
wherein
R' is a cyclic group selected from R", RB, Rc and R , each of which is
optionally
substituted with one or more R' groups;

R2 is hydrogen or C1-C2 alkyl;

R3 and R4 are each independently C1-Ce alkyl, C2 C8 alkenyl, CZ C8 alkynyl or
C3 C10
cycloalkyl, each of which is optionally substituted with one or more Rg
groups, or RE,
which is optionally substituted with one or more R9 groups, or hydrogen;


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or -NR3R4 forms RF, which is optionally substituted with one or more R'0
groups;
R5 is selected from -Y-C02R15 and -Y-R16;

R6, which may be attached at N' or N2, is C1-Cs alkyl, C1-Cs haloalkyl, C2 C6
alkenyl or
CZ C6 alkynyl, each of which is optionally substituted by C1-C6 alkoxy, C1-C6
haloalkoxy or a cyclic group selected from RJ, R", R' and R', or R6 is R", C3
C,
cycloalkyl or C3 C, halocycloalkyl, each of which is optionally substituted by
C1-C6
alkoxy or C,-C6 haloalkoxy, or R6 is hydrogen;

R' is halo, C1-C6 alkyl, C1-C6 haloalkyl, CZ Cs alkenyl, CZ C6 alkynyl, C3 C,0
cycloalkyl,
C3-C10 halocycloalkyl, phenyl, OR'2, OC(O)R'2, NO2, NR'2R'3, NR'zC(O)R'3,
NR'2C02R14, C(O)R 12, C02R 12, CONR12R'3 or CN;

R8 is halo, phenyl, C,-C6 alkoxyphenyl, OR12, OC(O)R 12, NO21 NR'2 R'3,
NR12C(O)R13,
NR'2C02R14, C(O)R 12, C02R 12, CONR12R13, CN, C3 C6 cycloalkyl, RG or R", the
last two
of which are optionally substituted with one or more R9 groups;

R9 is C,-C6 alkyl, C1-C6 haloalkyl or CO2R12;

R' is halo, C3-C, cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC(O)R12,
NO21
NR12R13, NR12C(O)R13, NR'2C02R14, C(O)R'2, CO2R'3, CONR'2 R13, CN, oxo, C,-C6
alkyl
or C1-C6 haloalkyl, the last two of which are optionally substituted by R";

R" is phenyl, NR12R13 or NR'2CO2R14;

R12 and R13 are each independently hydrogen, C,_C6 alkyl or C,-Cs haloalkyl;
R14 is C,_C6 alkyl or C,-C6 haloalkyl;


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R'5 is hydrogen or C1-C6 alkyl optionally substituted with one or more groups
selected
from phenyl, halo, OH, C1-Cs alkyloxy, NH2, NH(C,-Csalkyl) and N(C1-C6
alkyl)2;

R's is a carboxylic acid isostere selected from tetrazol-5-yl, 5-
trifluoromethyl-1,2,4-
triazol-3-yl, 5-(methylsulfonyl)-1,2,4-triazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-
oxadiazol-3-
yl, -SO2NHR" and -CONHR18;

R" is selected from C,-C6 alkyl, phenyl, -CO-(C1-Cs alkyl) and -CO-phenyl;
R'8 is selected from -SO2 (C,-C6 alkyl) and -SO2-phenyl;

R'4 and RJ are each independently a C3-C,o cycloalkyl or C3 C,o cycloalkenyl
group,
each of which may be either monocyclic or, when there are an appropriate
number
of ring atoms, polycyclic and which may be fused to either
(a) a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-
membered heteroaromatic ring containing up to three heteroatoms selected from
nitrogen, oxygen and sulphur, or
(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur;

RB and R" are each independently a phenyl or naphthyl group, each of which may
be
fused to
(a) a C5 C, cycloalkyl or C5 C, cycloalkenyl ring,
(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur, or
(c) a 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur;

R , R` and R" are each independently a monocyclic or, when there are an
appropriate number of ring atoms, polycyclic saturated or partly unsaturated
ring
system containing between 3 and 10 ring atoms, of which at least one is a


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heteroatom selected from nitrogen, oxygen and sulphur, which ring may be fused
to
a C5 C, cycloalkyl or C5 C7 cycloalkenyl group or a monocyclic aromatic ring
selected
from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up
to
three heteroatoms selected from nitrogen, oxygen and sulphur;

R and R' are each independently a 5- or 6-membered heteroaromatic ring
containing up to three heteroatoms independently selected from nitrogen,
oxygen
and sulphur, which ring may further be fused to
(a) a second 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur;
(b) C5 C, cycloalkyl or C5 C, cycloalkenyl ring;
(c) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur; or
(d) a benzene ring;
RE, RF and RG are each independently a monocyclic or, when there are an
appropriate number of ring atoms, polycyclic saturated ring system containing
between 3 and 10 ring atoms, of which at least one is a heteroatom selected
from
nitrogen, oxygen and sulphur;

R" is a 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms
independently selected from nitrogen, oxygen and sulphur; and

Y is a covalent bond, -CHZ O-CH2 , C,-C6 alkylenyl or C3-C, cycloalkylenyl;
a tautomer thereof or a pharmaceutically acceptable salt or solvate of said
compound or tautomer.

As used herein, alkylenyl indicates an alkyl-m,n-diyl unit where m and n are
the
same or different, such as methylene (-CH2-), ethylene (-CH2CH2-) and propane-
1,2-
diyl (-CH(CH3)CH2 ).


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As used herein, cycloalkylenyl indicates a cycloalkyl-m,n-diyl unit where m
and n are
the same or different, such as cyclopropane-1,1-diyl and cyclohexane-1,4-diyl.

Unless otherwise indicated, an alkyl or alkoxy group may be straight or
branched
and contain 1 to 8 carbon atoms, preferably I to 6 and particularly 1 to 4
carbon
atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl,
sec-butyl, pentyl and hexyl. Examples of alkoxy include methoxy, ethoxy,
isopropoxy and n-butoxy. ,

Unless otherwise indicated, an alkenyl or alkynyl group may be straight or
branched
and contain 2 to 8 carbon atoms, preferably 2 to 6 and particularly 2 to 4
carbon
atoms and may contain up to 3 double or triple bonds which may be conjugated.
Examples of alkenyl and alkynyl include vinyl, allyl, butadienyl and
propargyl.

Unless otherwise indicated, a cycloalkyl or cycloalkoxy group may contain 3 to
10
ring-atoms, may be either monocyclic or, when there are an appropriate number
of
ring atoms, polycyclic. Examples of cycloalkyl groups are cyclopropyl,
cyclopentyl,
cyclohexyl and adamantyl.

Unless otherwise indicated, a cycloalkenyl group may contain 3 to 10 ring-
atoms,
may be either monocyclic or, when there are an appropriate number of ring
atoms,
polycyclic and may contain up to 3 double bonds. Examples of cycloalkenyl
groups
are cyclopentenyl and cyclohexenyl.

Aryl includes phenyl, naphthyl, anthracenyl and phenanthrenyl.

Unless otherwise indicated, a heteroalicyclyl group contains 3 to 10 ring-
atoms up to
4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be
saturated or partially unsaturated. Examples of heteroalicyclyl groups are
oxiranyl,
azetidinyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl,


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imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl,
piperidinyl,
pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,
piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl.

Unless otherwise indicated, a heteroaryl group contains 3 to 10 ring-atoms up
to 4 of
which may be hetero-atoms such as nitrogen, oxygen and sulfur. Examples of
heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyi, pyrazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyi, pyridyl,
pyrimidinyl,
pyrazinyl, pyridazinyl, tetrazolyl, triazinyl. In addition, the term
heteroaryl includes
fused heteroaryl groups, for example benzimidazolyl, benzoxazolyl,
imidazopyridinyl,
benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl,
quinazolinyl,
quinoxalinyl, benzothiazolyi, phthalimido, benzofuranyl, benzodiazepinyl,
indolyl and
isoindolyl.

Halo means fluoro, chloro, bromo or iodo.

Haloalkyl includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, such as
2-bromoethyl, 2,2,2-trifluoroethyl, chlorodifluoromethyl and trichloromethyl.
Haloalkoxy includes monohaloalkoxy, polyhaloalkoxy and perhaloalkoxy, such as
2-bromoethoxy, 2,2,2-trifluoroethoxy, chlorodifluoromethoxy and
trichloromethoxy.
Halocycloalkyl includes monohalocycloalkyl, polyhalocycloalkyl and
perhalocycloalkyl.

Unless otherwise indicated, the term substituted means substituted by one or
more
defined groups. In the case where groups may be selected from a number of
alternative groups, the selected groups may be the same or different.

In one preferred embodiment, R' is RA, which is optionally substituted with
one or
more R' groups; and


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R' is a C3 C,o cycloalkyl group, which may be either monocyclic or, when there
are
an appropriate number of ring atoms, polycyclic, which may be fused to either
(a) a monocyclic aromatic ring selected from a benzene ring and a 5- or
6-membered heteroaromatic ring containing up to three heteroatoms selected
from
nitrogen, oxygen and sulphur, or
(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three
heteroatoms selected from nitrogen, oxygen and sulphur.

Preferably, R'4 is a monocyclic C3 C8 cycloalkyl group.
More preferably, R' is a monocyclic CS-C, cycloalkyl group.
Most preferably, R" is cyclopentyl or cyclohexyl.

In another preferred embodiment, R' is RB, which is optionally substituted
with one or
more R' groups.

Preferably, RB is phenyl.

In another preferred embodiment, R' is Rc, which is optionally substituted
with one or
more R' groups.

Preferably, R' is a monocyclic saturated or partly unsaturated ring system
containing
between 3 and 8 ring atoms, of which at least one is a heteroatom selected
from
nitrogen, oxygen and sulphur.

More preferably, R is a monocyclic saturated or partly unsaturated ring
system
containing between 5 and 7 ring atoms, of which at least one is a heteroatom
selected from nitrogen, oxygen and sulphur.



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Most preferably, Rc is a monocyclic saturated ring system containing between 5
and
7 ring atoms, of which at least one is a heteroatom selected from nitrogen,
oxygen
and sulphur.

In another preferred embodiment, R' is RD, which is optionally substituted
with one or
more R' groups.

Preferably, R is a 5- or 6-membered heteroaromatic ring containing up to
three
heteroatoms independently selected from nitrogen, oxygen and sulphur.

More preferably, R D is a 5-membered heteroaromatic ring containing a
heteroatom
selected from nitrogen, oxygen and sulphur and optionally up to two further
nitrogen
atoms in the ring, or a 6-membered heteroaromatic ring including 1, 2 or 3
nitrogen
atoms.

More preferably R D is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
isoxazolyl,
oxazolyl, isothiazolyl, thiazolyi, oxadiazolyl, pyridyl, pyridazinyl,
pyrimidyl or
pyrazinyl.

Most preferably, R is pyrazolyl, imidazolyi, isoxazolyl, oxazolyi,
oxadiazolyl, pyridyl,
pyridazinyl, pyrimidyl or pyrazinyl.

Preferably, R' is halo, C1-C6 alkyl, C1-C6 haloalkyl, OR12 or CONR12R13.

More preferably, R' is halo, C1-C3 alkyl, C1-C3 alkoxy, hydroxy or CONH(C,-C3
alkyl).
Most preferably, R' is fluoro, methyl, ethyl, hydroxy, methoxy, propoxy or
CONHMe.
Preferably, R2 is hydrogen or methyl.

More preferably, R2 is hydrogen.


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Preferably, R3 is hydrogen, C,-Cs alkyl, which is optionally substituted with
one or
more R8 groups, or RE, which is optionally substituted with one or more R9
groups;
and wherein RE is a monocyclic or, when there are an appropriate number of
ring
atoms, polycyclic saturated ring system containing between 3 and 7 ring atoms,
of
which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.
More preferably, R3 is hydrogen, C,-C4 alkyl, which is optionally substituted
with one
or more R8 groups, or RE, which is optionally substituted with one or more R9
groups;
and wherein RE is a monocyclic saturated ring system containing between 3 and
7
ring atoms, of which at least one is a heteroatom selected from nitrogen,
oxygen and
sulphur.

In one preferred embodiment, R3 is RE, which is optionally substituted with
one or
more R9 groups and wherein RE is a monocyclic saturated ring system containing
between 3 and 7 ring atoms containing one nitrogen atom.

More preferably, RE is azetidinyl, pyrrolidinyl or piperidinyl.

In another preferred embodiment, R3 is C,-C4 alkyl, which is optionally
substituted
with one or more Re groups and wherein R8 is halo, phenyl, C1-C6 alkoxyphenyl,
OR12, NR12R13, NR12COzR14, CO2R'2, CONR12R13, RG or R", the last two of which
are
optionally substituted with one or more R9 groups.

More preferably, R8 is hydroxy, methoxy, methoxyphenyl, NH2, NHMe, NMe2,
NHCO2`Bu, NMeCO2tBu, CO2H, CONHMe, RG or R", the last two of which are
optionally substituted with one or more R9 groups.

In one preferred embodiment, Re is RG, which is optionally substituted with
one or
more R9 groups and wherein RG is a monocyclic saturated ring system containing


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between 3 and 7 ring atoms, of which at least one is a heteroatom selected
from
nitrogen, oxygen and sulphur.

More preferably, RG is a monocyclic saturated ring system containing between 3
and
7 ring atoms containing one nitrogen atom and optionally one oxygen atom.

Most preferably, RG is pyrrolidinyl, piperidinyl or morpholinyl.

In another preferred embodiment, R8 is RH, which is optionally substituted
with one or
more R9 groups and wherein R" is a 5- or 6-membered heteroaromatic ring
containing up to two nitrogen atoms.

More preferably, R" is pyrazolyl.
Preferably, R9 is methyl or CO2tBu.

In another preferred embodiment, R3 is hydrogen or C,-C4 alkyl, which is
optionally
substituted with one or more R8 groups, or R3 is azetidinyl, pyrrolidinyl or
piperidinyl,
each of which is optionally substituted with one or more R9 groups, wherein
R8 is hydroxy, methoxy, methoxyphenyl, NH2, NHMe, NMe2, NHCO2'Bu, NMeCO2`Bu,
CO2H, CONHMe, pyrrolidinyl, piperidinyl, morpholinyl or pyrazolyl, the last
four of
which are optionally substituted with one or more R9 groups and wherein
R9 is methyl or CO2`Bu.

In one preferred embodiment, R4 is hydrogen, C,-C6 alkyl, C1-C6 haloalkyl, C2
C6
alkenyl or CZ C6 alkynyl.

More preferably, R4 is hydrogen, C,-C6 alkyl or C1-C6 haloalkyl.
Most preferably, R4 is hydrogen, methyl or ethyl.


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In another preferred embodiment, -NR3R4 forms RF, which is optionally
substituted
with one or more R10 groups and wherein RF is a monocyclic or, when there are
an
appropriate number of ring atoms, polycyclic saturated ring system containing
between 3 and 10 ring atoms containing at least one nitrogen atom and
optionally
one other atom selected from oxygen and sulphur.

More preferably, RF is a monocyclic or, when there are an appropriate number
of
ring atoms, polycyclic saturated ring system containing between 3 and 10 ring
atoms
containing one or two nitrogen atoms and optionally one other atom selected
from
oxygen and sulphur.

Most preferably, RF is selected from azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl,
morpholinyl, 3-azabicyclo[3.1.0]hex-3-yl, homopiperazinyl,
2,5-diazabicyclo[4.3.0]non-2-yl, 3,8-diazabicyclo[3.2:1]oct-3-yl,
3,8-diazabicyclo[3.2.1]oct-8-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 1,4-
diazabicyclo[4.3.0]non-4-yl and 1,4-diazabicyclo[3.2.2]non-4-yl.

Preferably R'0 is halo, OR12, NR12R13, NR'2C02R14, C02R13, oxo, C,-C6 alkyl or
C1-C6
haloalkyl, the last two of which are optionally substituted by R".

More preferably, R10 is halo, methyl, ethyl, isopropyl, hydroxy, methoxy, NH2,
NHMe,
NMe2, NHCOz`Bu, CO2H, CO2`Bu, oxo, benzyl, -CHaNH2, -CH2NHMe, CH2NMe2 or
-CH2NMeCO2`Bu.

In one preferred embodiment, R5 is -Y-C02R15. Preferably R'S is hydrogen or C1-
C3
alkyl. More preferably R'S is hydrogen. Preferably Y is a covalent bond or C1-
C6
alkylenyl. More preferably, Y is a covalent bond or methylene. Most preferably
Y
is a covalent bond

In another preferred embodiment, R5 is -Y-R16. Preferably R16 is a carboxylic
acid
isostere selected from -CONHR1e, tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-


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oxadiazol-3-yl. Preferably Y is a covalent bond or C,-C6 alkylenyl. More
preferably,
Y is a covalent bond or methylene

Preferably, R6 is positioned on N' to give the compound of formula (I"):
R R 2
R6 N
N N
N " R3
N N
R5 R4 (IA)

In an alternative embodiment of the present invention, R6 may be positioned on
N2 to
give the compound of formula (IB):

R1 NRz
R~ N~ N
N % ,Rs
N N
R5 R4 (IB)

Preferably, R6 is C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally
substituted
by C,-C6 alkoxy, C1-C6 haloalkoxy or a cyclic group selected from R', R` and
R"', or Rs
is R" or hydrogen;
RJ is a C3 C, monocyclic cycloalkyl group;
R` and R" are each independently a monocyclic, saturated or partly unsaturated
ring
system containing between 4 and 7 ring atoms, of which at least one is a
heteroatom selected from nitrogen, oxygen and sulphur; and
RA4 is a 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms
independently selected from nitrogen, oxygen and sulphur.


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More preferably, R6 is C,-C4 alkyl or C,-C4 haloalkyl, each of which is
optionally
substituted by C,-C4 alkoxy, C1-C4 haloalkoxy or a cyclic group selected from
RJ, R`
and R A, or R6 is R" or hydrogen;
R' is cyclopropyl or cyclobutyl;
R` and R" are each independently a monocyclic saturated ring system containing
either 5 or 6 ring atoms, of which at least one is a heteroatom selected from
nitrogen, oxygen and sulphur; and
R A is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected
from
nitrogen, oxygen and sulphur.

More preferably, R6 Is C,-C4 alkyl or C,-C4 haloalkyl, each of which is
optionally
substituted by C,-C4 alkoxy or a cyclic group selected from R', R` and R"", or
R6 is RN
or hydrogen;
R' is cyclopropyl or cyclobutyl;
R` and R" are each independently a monocyclic saturated ring system containing
either 5 or 6 ring atoms containing one heteroatom selected from nitrogen,
oxygen
and sulphur; and
R"' is a 5- or 6-membered heteroaromatic ring containing one nitrogen atom.
More preferably, R6 is C,-C4 alkyl or C,-C4 haloalkyl, each of which is
optionally
substituted by C,-C4 alkoxy, cyclopropyl, cyclobutyl, tetrahydrofuranyl,
tetrahydropyranyl or pyridinyl, or R6 is hydrogen or tetrahydropyranyl.

Most preferably, R6 is hydrogen, methyl, ethyl, isopropyl, isobutyl,
methoxyethyl,
methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, 2,2,2-trifluoroethyl,
tetrahydrofuranylmethyl, tetrahydropyranylmethyl, tetrahydropyranyl or
pyridinylmethyl.

Preferred embodiments of compounds of formula (I) are those that incorporate
two
or more of the foregoing preferences.


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Preferably R' is a cyclic group selected from R', RB, Rc and R , each of which
is
optionally substituted with one or more R' groups;

R2 is hydrogen or C,-C2 alkyl;

R3 is hydrogen, C,-C4 alkyl, which is optionally substituted with one or more
Rg
groups, or RE, which is optionally substituted with one or more R9 groups;

R4 is hydrogen, C,-C6 alkyl or C1-C6 haloalkyl;

or -NR3R4 forms RF, which is optionally substituted with one or more R'0
groups;
R5 is -Y-C02R15 or -Y-R16;

R6 is C,-C4 alkyl or C1-C4 haloalkyl, each of which is optionally substituted
by C,-C4
alkoxy, C1-C4 haloalkoxy or a cyclic group selected from RJ, R` and R"', or R6
is R" or
hydrogen;

R' is halo, C,-C6 alkyl, C1-C6 haloalkyl, C2 C6 alkenyl, C2 C6 alkynyl, C3 C10
cycloalkyl,
C3-C10 halocycloalkyl, phenyl, OR'2, OC(O)R'2, NO2, NR'2R'3, NR'aC(O)R'3,
NR'2COzR'4, C(O)R'2, C02R12, CONR12R13 or CN;

R8 is halo, phenyl, C,-C6 alkoxyphenyl, OR12, OC(O)R12, NO21 NR12R13,
NR12C(O)R13,
NR'2CO2R14, C(O)R12, C02R 12, CONR12R13, CN, RG or R", the last two of which
are
optionally substituted with one or more R9 groups;

R9 is C,-C6 alkyl, C1-Cs haloalkyl or C02R12;


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R10 is halo, C3 ,C, cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12,
OC(O)R12, NOz,
NR12R'3, NR12C(O)R13, NR12COaR14, C(O)R12, C02R13, CONR1zR13, CN, oxo, C1-C6
alkyl
or C,-Cs haloalkyl, the last two of which are optionally substituted by R";

R" is phenyl, NR'2 R13 or NR'2CO2R14;

R 12 and R13 are each independently hydrogen, C,_C6 alkyl or C1-C6 haloalkyl;
R'4 is C,_C6 alkyl or C,-C6 haloalkyl;

R15 is hydrogen or C1-C3 alkyl:

R16 is tetrazol-5-yl, 5-trifluoromethyl-1,2,4-triazol-3-yl or 2,5-dihydro-5-
oxo-1,2,4-
oxadiazol-3-yl;

RA is a monocyclic C3 Ce cycloalkyl group;
RB is phenyl;

Rc is a monocyclic saturated or partly unsaturated ring system containing
between 3
and 8 ring atoms, of which at least one is a heteroatom selected from
nitrogen,
oxygen and sulphur;

R D is a 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms
independently selected from nitrogen, oxygen and sulphur;

RE is a monocyclic saturated ring system containing between 3 and 7 ring
atoms, of
which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

RF and RG are each independently a monocyclic or, when there are an
appropriate
number of ring atoms, polycyclic saturated ring system containing between 3
and 10


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ring atoms, of which at least one is a heteroatom selected from nitrogen,
oxygen and
sulphur;

R" is a 5- or 6-membered heteroaromatic ring containing up to three
heteroatoms
independently selected from nitrogen, oxygen and sulphur;

RJ is cyclopropyl or cyclobutyl;

R` and R" are each independently a monocyclic saturated ring system containing
either 5 or 6 ring atoms, of which at least one is a heteroatom selected from
nitrogen, oxygen and sulphur;

R"" is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected
from
nitrogen, oxygen and sulphur; and

Y is a covalent bond or C,-C6 alkylenyl.

More preferably, R' is a cyclic group selected from RA, RB, Rc and R , each of
which
is optionally substituted with one or more R' groups;

R2 is hydrogen or C,-C2 alkyl;

R3 is hydrogen, C1-C4 alkyl, which is optionally substituted with one or more
Re
groups, or RE, which is optionally substituted with one or more R9 groups;

R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

or-NR3R4 forms RF, which is optionally substituted with one or more R'
groups;
R5 is -Y-CO2R'5;


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Rs is C1-C4 alkyl or C1-C4 haloalkyl, each of which is optionally substituted
by C1-C4
alkoxy, C1-C4 haloalkoxy or a cyclic group selected from R', R` and R"', or R6
is R" or
hydrogen;

R' is halo, C1-C6 alkyl, C1-C6 haloalkyl, OR12 or CONR12R13;

R8 is halo, phenyl, C1-C6 alkoxyphenyl, OR12 , NR12R13, NR12CO2R14, CO2R12,
CONR12 R13, RG or R", the last two of which are optionally substituted with
one or
more R9 groups;

R9 is C1-C6 alkyl, C1-C6 haloalkyl or C02R12;

R10 is halo, C3-C10 cycloalkyl, C3 C10 halocycloalkyl, phenyl, OR12, OC(O)R12,
NO2,
NR12R13, NR12C(O)R13, NR12C02R14, C(O)R12, C02R13, CONR12 R13 CN, oxo, C1-C6
alkyl
or C1-C6 haloalkyl, the last two of which are optionally substituted by R11;

R11 is phenyl, NR12 R13 or NR12CO2R14;

R 12 and R13 are each independently hydrogen, C1_C6 alkyl or C1-C6 haloalkyl;
R14 is C4_C6alkyl or C1-C6 haloalkyl;
R15 is hydrogen;

RA is a monocyclic C5 C, cycloalkyl group;
RB is phenyl;

Rc is a monocyclic saturated ring system containing between 5 and 7 ring
atoms, of
which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;


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R is a 5-membered heteroaromatic ring containing a heteroatom selected from
nitrogen, oxygen and sulphur and optionally up to two further nitrogen atoms
in the
ring, or a 6-membered heteroaromatic ring including 1, 2 or 3 nitrogen atoms;

RE is a monocyclic saturated ring system containing between 3 and 7 ring atoms
containing one nitrogen atom;

R' is a monocyclic or, when there are an appropriate number of ring atoms,
polycyclic saturated ring system containing between 3 and 10 ring atoms
containing
at least one nitrogen atom and optionally one other atom selected from oxygen
and
sulphur;

RG is a monocyclic saturated ring system containing between 3 and 7 ring
atoms, of
which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

R" is a 5- or 6-membered heteroaromatic ring containing up to two nitrogen
atoms;
R` and R" are each independently a monocyclic saturated ring system containing
either 5 or 6 ring atoms, of which at least one is a heteroatom selected from

nitrogen, oxygen and sulphur;

R"" is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected
from
nitrogen, oxygen and sulphur; and

Y is a covalent bond or methylene.

In an alternative embodiment of the present invention, the present invention
provides compounds of formula (I-AA)


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6 R
NI NH

N
NO I
~` Rs
N%\ N
R5 R4
(I-AA)
wherein
R' is a pyridyl optionally substituted with one or more C1-C6 alkyl groups;
R3 and R4 are each independently hydrogen or C1-C6 alkyl;

R5 is -CONHR'e;

R6 is C1-C6 alkyl, optionally substituted by a substituent selected from -OH,
C3-C6
cycloalkyloxy, C1-Cs alkoxy and C1-C6 haloalkoxy;

R18 is selected from the group consisting of -S02 (C,-C6 alkyl) and -S02-
phenyl;
and tautomers thereof or a pharmaceutically acceptable salts, or solvates of
said
compounds or tautomers.
In another embodiment of the compounds of formula I-AA, R' is 2-pyridinyl
substituted with one or more methyl. In another embodiment of the compounds of
formula I-AA, R3 and R4 are independently selected from the group consisting
of
methyl, ethyl, propyl, and isopropyl. In another embodiment of the compounds
of
formula I-AA, R18 is selected from the group consisting of -SO2CH3, and -
SO2CH2CH3. In another embodiment of the compounds of formula I-AA, R6 is
ethyl,
optionally substituted by a subsituent selected from the group consisting of
hydroxyl,
methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy,
difluoromethoxy, difluoroethoxy, difluoropropoxy, trifluoromethoxy,
trifluoroethoxy,
trifluoropropoxy, and cyclobutyloxy.

In another embodiment of the compounds of formula I-AA, R' pyridinyl is
substituted
with one or more methyl;


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R3 and R4 are independently selected from the group consisting of hydrogen,
methyl,
ethyl, propyl and isopropyl;

R6 is ethyl, optionally substituted by a subsituent selected from the group
consisting
of -OH, C3-C6 cycloalkyloxy, C1-C6 alkoxy and C1-C6 haloalkoxy; and

R18 is selected from the group consisting of-SO2CH3, and -SO2CH2CH3.

In another alternative embodiment of the present invention, the present
invention
provides compounds of formula (I-BB)

R6A
-N
HN ~
N
N O
%\ , R3
N~~ N
R
,NH (I-BB)
R18

wherein
R3 and R4 are each independently selected from the group consisting of methyl,
ethyl, and isopropyl;

R6A is selected from the group consisting of methyl, ethyl, propyl,
fluoromethyl,
fluoroethyl, fluoropropyl, difluoroethyl, difluoropropyl, trifluoroethyl, and
trifluoropropyl; and

R18 is selected from the group consisting of-SO2CH3, and -SO2CH2CH3.
Most preferred compounds are:


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methyl 5-((1 S,4S)-2,5-diazabicyclo[2.2.1 ]hept-2-yl)-1-(2-ethoxyethyl)-7-(4-
methyl-
pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,

methyl 1 -(2-eth oxyethyl)-5-(N-iso propyl-N-methylamino)-7-(6-methyl pyrid i
n-2-
ylamino)-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,

ethyl 1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-
ylamino)-1 H-
pyrazolo[4,3-d]pyrimidine-3-carboxylate,

2-(dimethylamino)ethyl 5-dimethylamino-l-(2-ethoxyethyl)-7-(4-methylpyridin-2-
ylamino)-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylate,
1-(2-ethoxyethyl)-5-(N-methyl-N-propylamino)-7-(4-methylpyridin-2-ylamino)-1 H-

pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1-(2-propoxy-
ethyl)-
1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
7-(4,6-dimethylpyridin-2-ylamino)-1-(2-ethoxyethyl)-5-(N-isopropyl-N-methyl-
amino)-
1 H-pyrazolo[4,3-a']pyrimidine-3-carboxylic acid,

5-(N-cyclobutyl-N-methylamino)-1 -(2-ethoxyethyl)-7-(4-methylpyridin-2-
ylamino)-1 H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-isopropylamino-7-(4-methylpyridin-2-ylamino)-1 H-
pyrazolo[4,3-
d]pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(2-methoxypyrimidin-4-ylamino)-1
H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,



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3-[1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-
ylamino)-
1 H-pyrazolo[4,3-d]pyrimidin-3-yl]-2H-1,2,4-oxadiazol-5-one,
3-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1
H-
pyrazolo[4,3-d]pyrimidin-3-yl]-2H-1,2,4-oxadiazol-5-one,
1-(2-ethoxyethyl)-7-(4-fluoro-3-methylphenylamino)-5-(N-isopropyl-N-
methylamino)-
1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-fluoro-3-methylphenylamino)-1
H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
7-(3,4-dimethylphenylamino)-1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-1 H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-(cyclopropylmethoxy)ethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methyl-
pyridin-
2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
1-(2-(cyclopropylmethoxy)ethyl )-5-(N-ethyl-N-methylam ino)-7-(4-methyl-pyrid
i n-2-
ylamino)-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-
1 H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,

1-(2-isopropoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-
ylamino)-
1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid,
N-[1-(2-ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7=(4=methylpyridin-2-
ylamino)-
1 H-pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide, and



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N-[1-(2-ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1
H-
pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide
and tautomers thereof and pharmaceutically acceptable salts or solvates of
said

compounds or tautomers.

Pharmaceutically acceptable salts of the compounds of formula (I) include the
acid
addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts.
Examples include the acetate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,
edisylate,
esylate, formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,
oxalate,
paimitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate
salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples
include the aluminium, arginine, benzathine, calcium, choline, diethylamine,
diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc salts.

For a review on suitable salts, see "Handbook of Pharmaceutical Salts:
Properties,
Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
A pharmaceutically acceptable salt of a compound of formula-(I) may be readily-

prepared by mixing together solutions of the compound of formula (I) and the
desired acid or base, as appropriate. The salt may precipitate from solution
and be


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collected by filtration or may be recovered by evaporation of the solvent. The
degree
of ionisation in the salt may vary from completely ionised to almost non-
ionised.

The compounds of the invention may exist in both unsolvated and solvated
forms.
The term 'solvate' is used herein to describe a molecular complex comprising
the
compound of the invention and one or more pharmaceutically acceptable solvent
molecules, for example, ethanol. The term `hydrate' is employed when said
solvent
is water.

Included within the scope of the invention are complexes such as clathrates,
drug-
host inclusion complexes wherein, in contrast to the aforementioned solvates,
the
drug and host are present in stoichiometric or non-stoichiometric amounts.
Also
included are complexes of the drug containing two or more organic and/or
inorganic
components which may be in stoichiometric or non-stoichiometric amounts. The
resulting complexes may be ionised, partially ionised, or non-ionised. For a
review of
such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
Hereinafter all references to compounds of formula (I) include references to
salts,
solvates and complexes thereof and to solvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (I) as
hereinbefore
defined, polymorphs, prodrugs, and isomers thereof (including optical,
geometric
and tautomeric isomers) as hereinafter defined and isotopically-labeled
compounds
of formula (I).

Also within the scope of the invention are so-called `prodrugs' of the
compounds of
formula (I). Thus certain derivatives of compounds of formula (I) which may
have
little or no pharmacological activity themselves can, when administered into
or onto
the body, be converted into compounds of formula (I) having the desired
activity, for
example, by hydrolytic cleavage. Such derivatives are referred to as
`prodrugs'.
Further information on the use of prodrugs may be found in `Pro-drugs as Novel


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Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and
'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche,
American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by
replacing appropriate functionalities present in the compounds of formula (I)
with
certain moieties known to those skilled in the art as `pro-moieties' as
described, for
example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include:

(i) where the compound of formula (I) contains a carboxylic acid functionality
(-COOH), an ester thereof, for example, replacement of the hydrogen with (C,-
C8)alkyl;

(ii) where the compound of formula (I) contains an alcohol functionality (-
OH), an
ether thereof, for example, replacement of the hydrogen with (C,-
C6)alkanoyloxymethyl; and

(iii) where the compound of formula (I) contains a primary or secondary amino
functionality (-NH2or -NHR where RO H), an amide thereof, for example,
replacement of one or both hydrogens with (C,-C,o)alkanoyl.

Further examples of replacement groups in accordance with the foregoing
examples
and examples of other prodrug types may be found in the aforementioned
references.

Finally, certain compounds of formula (I) may themselves act as prodrugs of
other
compounds of formula (I).



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Compounds of formula (I) containing one or more asymmetric carbon atoms can
exist as two or more stereoisomers. Where a compound of formula (I) contains
an
alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are
possible.
Where the compound contains, for example, a keto or oxime group or an aromatic
moiety, tautomeric isomerism (`tautomerism') can occur. It follows that a
single
compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers,
geometric
isomers and tautomeric forms of the compounds of formula (I), including
compounds
exhibiting more than one type of isomerism, and mixtures of one or more
thereof.
Also included are acid addition or base salts wherein the counterion is
optically
active, for example, D-lactate or L-lysine, or racemic, for example, DL-
tartrate or DL-
arginine.

Cisltrans isomers may be separated by conventional techniques well known to
those
skilled in the art, for example, chromatography and fractional
crystallisation.
Conventional techniques for the preparation/isolation of individual
enantiomers
include chiral synthesis from a suitable optically pure precursor or
resolution of the
racemate (or the racemate of a salt or derivative) using, for exampie, chiral
high
pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a
suitable
optically active compound, for example, an alcohol, or, in the case where the
compound of formula (I) contains an acidic or basic moiety, an acid or base
such as
tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may
be
separated by chromatography and/or fractional crystallization and one or both
of the
diastereoisomers converted to the corresponding pure enantiomer(s) by means
well
known to a skilled person.



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Ch'iral compounds of the invention (and chiral precursors thereof) may be
obtained
in enantiomerically-enriched form using chromatography, typically HPLC, on an
asymmetric resin with a mobile phase consisting of a hydrocarbon, typically
heptane
or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and
from
0 to 5% of an alkylamine, typically 0.1 lo diethylamine. Concentration of the
eluate
affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniques known
to those skilled in the art - see, for example, "Stereochemistry of Organic
Compounds" by E L Eliel (Wiley, New York; 1994).

The present invention includes all pharmaceutically acceptable isotopically-
labelled
compounds of formula (I) wherein one or more atoms are replaced by atoms
having
the same atomic number, but an atomic mass or mass number different from the
atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention
include isotopes of hydrogen, such as 2 H and 3H, carbon, such as "C,13C
and14C,
chlorine, such as 36C1, fluorine, such as18F, iodine, such as1231 and'2SI,
nitrogen, such
as13N and15N, oxygen, such as150, "O and180, phosphorus, such as 32P, and
sulphur, such as S.

Certain isotopically-labelled compounds of formula (I), for example, those
incorporating a radioactive isotope, are useful in drug and/or substrate
tissue
distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-
14, i.e. 14C,
are particularly useful for this purpose in view of their ease of
incorporation and
ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford
certain
therapeutic advantages resulting from greater metabolic stability, for
example,


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increased in vivo half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.

I
Substitution with positron emitting isotopes, such as "C, 'gF,150 and 13N, can
be
useful in Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be prepared by
conventional techniques known to those skilled in the art or by processes
analogous
to those described in the accompanying Examples and Preparations using an
appropriate isotopically-labeled reagents in place of the non-labeled reagent
previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include
those
wherein the solvent of crystallization may be isotopically substituted, e.g.
D20, d6-
acetone, ds DMSO.

Compounds of the invention intended for pharmaceutical use may be administered
as crystalline or amorphous products. They may be obtained, for example, as
solid
plugs, powders, or films by methods such as precipitation, crystallization,
freeze
drying, spray drying, or evaporative drying. Microwave or radio frequency
drying may
be used for this purpose.

The compounds of formula (I) are inhibitors of PDE5. Accordingly, in a further
aspect the present invention provides for the use of a compound of formula
(I), or a
tautomer, salt or solvate thereof, as a pharmaceutical agent, and particularly
as a
therapeutic agent for the treatment of a condition where inhibition of PDE5 is
known,
or can be shown, to produce a beneficial effect.

The term "treatment" includes palliative, curative and prophylactic treatment.


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Conditions suitable for treatment with the compounds of the invention include
hypertension (including essential hypertension, -pulmonary hypertension,
secondary
hypertension, isolated systolic hypertension, hypertension associated with
diabetes,
hypertension associated with atherosclerosis, and renovascular hypertension),
congestive heart failure, angina (including stable, unstable and variant
(Prinzmetal)
angina), stroke, coronary artery disease, congestive heart failure, conditions
of
reduced blood vessel patency (such as post-percutaneous coronary angioplasty),
peripheral vascular disease, atherosclerosis, nitrate-induced tolerance,
nitrate
tolerance, diabetes, impaired glucose tolerance, metabolic syndrome, obesity,
sexual dysfunction (including male erectile disorder, impotence, female sexual
arousal disorder, clitoral dysfunction, female hypoactive sexual desire
disorder,
female sexual pain disorder, female sexual orgasmic dysfunction and sexual
dysfunction due to spinal cord injury), premature labour, pre-eclampsia,
dysmenorrhea, polycystic ovary-syndrome, benign prostatic hyperplasia, bladder
outlet obstruction, incontinence, chronic obstructive pulmonary disease, acute
respiratory failure, bronchitis, chronic asthma, allergic asthma, allergic
rhinitis, gut
motility disorders (including irritable bowel syndrome), Kawasaki's syndrome,
multiple sclerosis, Alzheimer's disease, psoriasis, skin necrosis, scarring,
fibrosis,
pain (particularly neuropathic pain), cancer, metastasis, baldness, nutcracker
oesophagus, anal fissure and haemorrhoids.

In a further aspect, the present invention provides for the use of a compound
of
formula (I), or a tautomer, salt or solvate thereof, for the manufacture of a
medicament for the treatment of such a condition.

The compounds of the present invention may be used alone or in combination
with
other therapeutic agents. When used in combination with another therapeutic
agent
the administration of the two agents may be simultaneous or sequential.
Simultaneous administration includes the administration of a single dosage
form that
comprises both agents and the administration of the two agents in separate
dosage
forms at substantially the same time. Sequential administration includes the


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administration of the two agents according to different schedules provided
that there
is an overlap in the periods during which the treatment is provided. Suitable
agents
with which the compounds of formula (I) can be co-administered include
aspirin,
angiotensin II receptor antagonists (such as losartan, candesartan,
telmisartan,
valsartan, irbesartan and eprosartan), calcium channel blockers (such as
amiodipine), beta-blockers (i.e. beta-adrenergic receptor antagonists such as
sotalol,
proporanolol, timolol, antenolol, carvedilol and metoprolol), C11027, CCR5
receptor
antagonists, imidazolines, sGCa's (soluble guanylate cyclase activators)
antihypertensive agents, diuretics (such as hydrochlorothiazide, torsemide,
chlorothiazide, chlorthalidone and amiloride), alpha adrenergic antagonists
(such as
doxazosin), ACE (angiotensin converting enzyme) inhibitors (such as quinapril,
enalapril, ramipril and lisinopril), aldosterone receptor antagonists (such as
eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic
agents (such as insulin, sulfonylureas (such as glyburide, glipizide and
glimepiride),
glitazones (such as rosiglitazone and pioglitazone) and metformin),
cholesterol
lowering agents (such as atorvastatin, pravastatin, lovastatin, simvastatin,
clofibrate
and rosuvastatin), and alpha-2-delta ligarids (such as gabapentin, pregabalin,
[(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-
aminomethyl-
cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1 H-tetrazol-5-ylmethyl)-
cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-
acetic
acid, (1a,3a,5a)-(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-
3-
aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid,
(3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-amino-5-methyl-octanoic
acid).

The compounds of formula (I) may be administered alone or in combination with
one
or more other compounds of the invention or in combination with one or more
other
drugs (or as any combination thereof). Generally, tliey will be administered-
as a
formulation in association with one or more pharmaceutically acceptable
excipients.
The term "excipient" is used herein to describe any ingredient other than the
compound(s) of the invention. The choice of excipient will to a large extent
depend


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on factors such as the particular mode of administration, the effect of the
excipient
on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the
present
invention and methods for their preparation will be readily apparent to those
skilled
in the art. Such compositions and methods for their preparation may be found,
for
example, in `Remington's Pharmaceutical Sciences', 19th Edition (Mack
Publishing
Company, 1995).

The compounds of the invention may be administered orally. Oral administration
may involve swallowing, so that the compound enters the gastrointestinal
tract, or
buccal or sublingual administration may be employed by which the compound
enters
the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such
as
tablets, capsules containing particulates, liquids, or powders, lozenges
(including
liquid-filled), chews, multi- and nano-particulates, gels, solid solution,
liposome, films
(including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such
formulations may be employed as fillers in soft or hard capsules and typically
comprise a carrier, for exampie, water, ethanol, polyethylene glycol,
propylene
glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents
and/or
suspending agents. Liquid formulations may also be prepared by the
reconstitution
of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-
disintegrating dosage forms such as those described in Expert Opinion in
Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).



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For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to
80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage
form.
In addition to the drug, tablets generally contain a disintegrant. Examples of
disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose,
calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone,
polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower
alkyl-
substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium
alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%,
preferably

from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet
formulation.
Suitable binders include microcrystalline cellulose, gelatin, sugars,
polyethylene
glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised
starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also
contain diluents, such as lactose (monohydrate, spray-dried monohydrate,
anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol,
microcrystalline
cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium
lauryl
sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
When
present, surface active agents may comprise from 0.2 wt% to 5 wt% of the
tablet,
and glidants may comprise from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium
stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium
stearate with sodium lauryl sulphate. Lubricants generaliy comprise from 0.25
wt%
to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring
agents,
preservatives and taste-masking agents.


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Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90
wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to
about
wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

5 Tablet blends may be compressed directly or by roller to form tablets.
Tablet blends
or portions of blends may alternatively be wet-, dry-, or melt-granulated,
melt
congealed, or extruded before tabletting. The final formulation may comprise
one or
more layers and may be coated or uncoated; it may even be encapsulated.

10 The formulation of tablets is discussed in "Pharmaceutical Dosage Forms:
Tablets,
Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN
0-
8247-6918-X).

Solid formulations for oral administration may be formulated to be immediate
and/or
modified release. Modified release formulations include delayed-, sustained-,
pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations for the purposes of the invention are
described in US Patent No. 6,106,864. Details of other suitable release
technologies
such as high energy dispersions and osmotic and coated particles are to be
found in
Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of
chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly into the
blood
stream, into muscle, or into an internal organ. Suitable means for parenteral
administration include intravenous, intraarterial, intraperitoneal,
intrathecal,
intraventricular, intraurethral, intrasternal, intracranial, intramuscular and
subcutaneous. Suitable devices for parenteral administration include needle
(including microneedle) injectors, needle-free injectors and infusion
techniques.


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Parenteral formulations are typically aqueous solutions which may contain
excipients
such as salts, carbohydrates and buffering agents (preferably to a pH of from
3 to 9),
but, for some applications, they may be more suitably formulated as a sterile
non-
aqueous solution or as a dried form to be used in conjunction with a suitable
vehicle
such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for
example, by
lyophilisation, may readily be accomplished using standard pharmaceutical
techniques well known to those skilled in the art.

The solubility of compounds of formula (1)'used in the preparation of
parenteral
solutions may be increased by the use of appropriate formulation techniques,
such
as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled-, targeted and programmed release. Thus compounds of the
invention may be formulated as a solid, semi-solid, or thixotropic liquid for
administration as an implanted depot providing modified release of the active
compound. Examples of such formulations include drug-coated stents and PGLA
microspheres.

The compounds of the invention may also be administered topically to the skin
or
mucosa, that is, dermally or transdermally. Typical formulations for this
purpose
include gels, hydrogels, lotions, solutions, creams, ointments, dusting
powders,
dressings, foams, films, skin patches, wafers, implants, sponges, fibres,
bandages
and microemulsions. Liposomes may also be used. Typical carriers include
alcohol,
water, mineral oil, liquid petrolatum, white petrolatum, glycerin,
polyethylene glycol
and propylene glycol. Penetration enhancers may be incorporated - see, for
example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).


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Other means of topical administration include delivery by electroporation,
iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free
(e.g.
PowderjectT"', BiojectT"', etc.) injection.

Formulations for topical administration maybe formulated to be immediate
and/or
modified release. Modified release formulations include delayed-, sustained-,
pulsed-, controlled-, targeted and programmed release.

The compounds of the invention can also be administered intranasally or by
inhalation, typically in the form of a dry powd'er (either alone, as a
mixture, for
example, in a dry blend with lactose, or as a mixed component particle, for
example,
mixed with phospholipids, such as phosphatidylcholine) from a dry powder
inhaler or
as an aerosol spray from a pressurised container, pump, spray, atomiser
(preferably
an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser,
with or
without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise
a
bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a
solution
or suspension of the compound(s) of the invention comprising, for example,
ethanol,
aqueous ethanol, or a suitable alternative agent for dispersing, solubilising,
or
extending release of the active, a propellant(s) as solvent and an optional
surfactant,
such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is
micronised to a size suitable for delivery by inhalation (typically less than
5 microns).
This may be achieved by any appropriate comminuting method, such as spiral jet
milling, fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high
pressure homogenisation, or spray drying.



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Capsules (made, for example, from gelatin or HPMC), blisters and cartridges
for use
in an inhaler or insufflator may be formulated to contain a powder mix of the
compound of the invention, a suitable powder base such as lactose or starch
and a
performance modifier such as /-leucine, mannitol, or magnesium stearate. The
lactose may be anhydrous or in the form of the monohydrate, preferably the
latter.
Other suitable excipients include dextran, glucose, maltose, sorbitol,
xylitol, fructose,
sucrose and trehalose.

A suitable solution formulation for use in an atomiser using
electrohydrodynamics to
produce a fine mist may contain from 1 pg to 10mg of the compound of the
invention
per actuation and the actuation volume may vary from 1 pl to 100pl. A typical
formulation may comprise a compound of formula (I), propylene glycol, sterile
water,
ethanol and sodium chloride. Alternative solvents which may be used instead of
propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as
saccharin or saccharin sodium, may be added to those formulations of the
invention
intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be
immediate and/or modified release using, for example, poly(DL-lactic-
coglycolic acid
(PGLA). Modified release formulations include delayed-, sustained-,
pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined
by
means of a valve which delivers a metered amount. Units in accordance with the
invention are typically arranged to administer a metered dose or "pufP"
containing
from 1 pg to 20mg of the compound of formula (I). The overall daily dose will
typically be in the range 1 pg to 80mg which may be administered in a single
dose or,
more usually, as divided doses throughout the day.


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The compounds of the invention may be administered rectally or vaginally, for
example, in the form of a suppository, pessary, or enema. Cocoa butter is a
traditional suppository base, but various alternatives may be used as
appropriate.

Formulations for rectal/vaginal administration may be formulated to be
immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may also be administered directly to the eye or
ear,
typically in the form of drops of a micronised suspension or solution in
isotonic, pH-
adjusted, sterile saline. Other formulations suitable for ocular and aural
administration include ointments, biodegradable (e.g. absorbable gel sponges,
collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and
particulate or vesicular systems, such as niosomes or liposomes. A polymer
such as
crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a
cellulosic
polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or
methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum,
may
be incorporated together with a preservative, such as benzalkonium chloride.
Such
formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled-, targeted, or programmed release.

The compounds of the invention may be combined with soluble macromolecular
entities, such as cyclodextrin and suitable derivatives thereof or
polyethylene glycol-
containing polymers, in order to improve their solubiiity, dissolution rate,
taste-
masking, bioavailability and/or stability for use in any of the aforementioned
modes
of administration.



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Drug-cyclodextrin complexes, for example, are found to be generally useful for
most
dosage forms and administration routes. Both inclusion and non-inclusion
complexes may be used. As an alternative to direct complexation with the drug,
the
cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent,
or
solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-

cyclodextrins, examples of which may be found in International Patent
Applications
Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Inasmuch as it may desirable to administer a combination of active compounds,
for
example, for the purpose of treating a particular disease or condition, it is
within the
scope of the present invention that two or more pharmaceutical compositions,
at
least one of which contains a compound in accordance with the invention, may
conveniently be combined in the form of a kit suitable for coadministration of
the
compositions.

Thus the kit of the invention comprises two or more separate pharmaceutical
compositions, at least one of which contains a compound of formula ... in
accordance with the invention, and means for separately retaining said
compositions, such as a container, divided bottle, or divided foil packet. An
example
of such a kit is the familiar blister pack used for the packaging of tablets,
capsules
and the like.

The kit of the invention is particularly suitable for administering different
dosage
forms, for example, oral and parenteral, for administering the separate
compositions
at different dosage intervals, or for titrating the separate compositions
against one
another. To assist compliance, the kit typically comprises directions for
administration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of
the
invention is typically in the range 0.1 mg to 500 mg depending, of course, on
the
mode of administration. For example, oral administration may require a total
daily


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dose of from 0.1 mg to 500 mg, while an intravenous dose may only require from
0.01 mg to 50mg. The total daily dose may be administered in single or divided
doses.

These dosages are based on an average human subject having a weight of about
65kg to 70kg. The physician will readily be able to determine doses for
subjects
whose weight falls outside this range, such as infants and the elderly.

Compounds of the invention may be prepared, in known manner in a variety of
ways.
In the following reaction schemes and hereafter, unless otherwise stated R' to
R6 are
as defined in the first aspect. These processes form further aspects of the
invention.
a) Compounds of formula (Ic), i.e. compounds of formula (I) wherein R5 is
-Y-C02R15 and R15 is H, may generally be prepared from the corresponding
esters of
formula (II) wherein R" is an alkyl group (particularly a methyl, ethyl, or
tert-butyl
group) or a benzyl group, as illustrated in Scheme 1.

Scheme 1

R~N~R2 R~NR2
R6 N ~ k N -~ R6 N N

N i R3 N i R3
NN'
R150 C-Y N R4 HO C-Y R4
2 2
(II) (IC)
When R15 is methyl or ethyl the conversion may conveniently be accomplished by
treating the compound of formula (II) with an alkaline metal hydroxide such as
lithium, sodium or potassium hydroxide in a suitable solvent at a temperature
of
between about 10 C and the boiling point of the solvent. Suitable solvents
include
water, methanol, ethanol and mixtures of water with methanol, ethanol,
tetrahydrofuran and dioxan. When R15 is tert-butyl the conversion may be


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accomplished by treating the compound of formula (II) with an acid such as
hydrogen chloride or trifluoroacetic acid in a suitable solvent at a
temperature of
between 0 C and ambient temperature. Suitable solvents include dioxan and
dichloromethane. When R15 is benzyl the conversion may conveniently be
accomplished by treating the compound of formula (II) with an alkaline metal
hydroxide as discussed above, or by hydrogenolysis using molecular hydrogen or
a
suitable hydrogen donor such as ammonium formate in the presence of a
transition
metal or transition metal salt catalyst such as palladium-on-carbon, in a
suitable
solvent, such as methanol.

When there is a functional group in another part of the structure of (1 ) that
is
protected, such as an amino group in R' or R3, it may be convenient to select
R15and
the protecting group such that they may both be removed in a single operation.
For
example, if there is an amine group protected by a BOC group, then selecting
R'S to
be tert-butyl will allow both unmasking oprerations to be achieved with a
single acid
treatment. Similarly, if benzyloxycarbonyl is the preferred amine protecting
group,
the use of benzyl for R'5 permits simultaneous unmasking in a single
hydrogenolysis
step. Alternatively, the protecting group and R15 may be chosen so as to be
`orthogonal', i.e. each is stable to the conditions used to cleave the other.
Unmasking is then a two stage process, but the intermediate can be subject to
a
purification step.

b) Compounds of formula (I ), i.e. compounds of formula (I) wherein R5 is
-Y-C02R15 and R'5 is not hydrogen may be prepared by esterification of the
corresponding acid of formula (1 ), as illustrated in Scheme 2, but this step
is only
necessary if the nature of R15 is such that the ester group -C02R 15 is not
compatible
with one or more of the synthetic steps used.


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Scheme 2
NR
1 N/R 2 R\ 1 2
R\

R 6 N N R 6 N N

N~ R3 N R3
' Ni ~N
HO C-Y N R4 R'50 C_Y R4
2 2
(IC) (I ; R15 # hydrogen)

The conversion may conveniently be accomplished by treating a mixture of the
acid
of formula (Ic) and an alcohol R15-OH in a suitable solvent with a condensing
agent
such as a carbodiimide, e.g. dicyclohexylcarbodiimide or N-(3-
dimethylaminopropyl)-
N'-ethylcarbodiimide, optionally in the presence of 4-dimethylaminopyridine,
at a
temperature of between 0 C and the boiling point of the solvent. Suitable
solvents
include dichloromethane and dimethylformamide. Alternatively, the acid of
formula
(Ic) may be converted to the corresponding acid chloride using thionyl
chloride or
oxalyl chloride and then treated with the alcohol R15-OH.

c) Compounds of formula (II") and (IIB), wherein R6A is as defined for R6
except
that it cannot be hydrogen, i.e. compounds of formula (II) wherein R6 is other
than H,
can be prepared from compounds of formula (II'), i.e. compounds of formula
(II)
wherein R6 is H, as illustrated in Scheme 3.


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Scheme 3
N
R6A R\ 2

/N N (IIA)
N
1 2 / \ R3
R~ R N N
H N R1502C- R4
N
N N
-~
,~ 3 --
N%\ N 1 2

R150 C-Y R4 R\N/R
2
(IIc) 6A N~ N g
R-N ~ R3 (II )
N N
R150 C_Y R4
2

The compound of formula (IIc) is treated with a base such as an alkaline metal
carbonate or bicarbonate, for example potassium carbonate or caesium
carbonate,
or a tertiary amine, for example triethylamine, diisopropylethylamine or
pyridine, and
the appropriate chloride (R6A-CI), bromide (R6A-Br), iodide (R6A-I), mesylate
(R6A-OSOZCH3) or tosylate (R6A-OSOzTol) in a suitable solvent at a temperature
of
between -700C and 100 C. Suitable solvents include ethers such as
tetrahydrofuran and dioxan, dimethylformamide and acetonitrile. Stronger bases
such as sodium hydride, potassium tert-butoxide and sodium or potassium
hexamethyidisilazide may also be used. Alternatively, the transformation may
be
achieved using the Mitsunobu reaction, in which a solution of the compound of
formula (11 ) and the appropriate alcohol R6A-OH in a suitable solvent is
treated with
triphenylphosphine and a dialkylazodicarboxylate such as diethyl
azodicarboxylate
or diisopropyl azodicarboxylate. A preferred solvent is tetrahydrofuran. The
reaction is preferably performed at a temperature of between -10 C and ambient
temperature.


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When the reaction gives a mixture of the two products (IIA) and (IIB), these
can be
separated using standard techniques.

The introduction of R6 at this stage of the synthetic sequence is not always
necessary. It is often more convenient to introduce R6 at an early stage and
carry it
through to the final product.

d) Compounds of formula (II) can be prepared from the corresponding
monochlorides of formula (III) by reaction with HNR3R4 as illustrated in
Scheme 4.
Scheme 4

R~NR2 R~N,R2
R6 N N HNR3R4 R6 N
N~ N N
s
R
N CI NN
R15~ C-V R15~ C_y R4
2 2

(III) (II)
A solution of the monochloride (III) and the amine'HNR3R`' in a suitable
dipolar
aprotic solvent are stirred at elevated temperature for between 1 and 24
hours.
Suitable solvents include dimethylsulfoxide, dimethylformamide and N-
methylpyrrolidinone. An excess of a tertiary amine such as N-
ethyidiisopropylamine, N-methylmorpholine or triethylamine and/or a fluoride
source
such as caesium fluoride or tetraethylammonium fluoride may optionally be
included.
It is sometimes necessary to perform the reaction at elevated pressure in a
closed
vessel, particularly when the amine HNR3R4 or the solvent is volatile. It will
be
appreciated that any functional groups in HNR3R4, and particularly any primary
or
secondary amine groups, may need to be protected in order to allow this
reaction to
proceed successfully.


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Preferably, the monochloride is treated with 3-5 equivalents of the amine
HNR3R4
and optionally 2-5 equivalents of N-ethyldiisopropylamine in dimethylsulfoxide
or N-
methylpyrrolidinone, optionally in the presence of caesium fluoride or
tetraethylammonium fluoride, at 80-125 C for 12-18 hours, optionally in a
closed

vessel.

Alternatively, the compounds of formula (III) may be hydrolysed as described
inI part
a) above to provide the corresponding carboxylic acid of formula (IV) which is
then
treated with amine HNR3R4 to provide compounds of formula (f), as illustrated
in

scheme 4a.
Scheme 4a

R~N~R2
R R. ~ R2
N N

CI R6 N
N
R150 C-Y N
2
N CI
HO2C-Y
(III) (IV)
R~N,R2
R 6 N N
~ N
3
R

HO2C-Y R4
(IC)
Preferably, the monochloride (IV) is treated with 3-5 equivalents of the amine
HNR3R4 and optionally 2-5 equivalents of N-ethyldiisopropylamine in
dimethylsulfoxide or N-methylpyrrolidinone, optionally in the presence of
caesium
fluoride or tetraethylammonium fluoride, at 80-125 C for 12-18 hours,
optionally in a
closed vessel.


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e) Compounds of formula (III) can be prepared from the corresponding
dichlorides of formula (V) by reaction with HNR'Ra as illustrated in Scheme 5.

Preferably, the monochloride is treated with 3-5 equivalents of the amine
HNR3R4
and optionally 2-5 equivalents of N-ethyldiisopropylamine in dimethylsulfoxide
or N-
methylpyrrolidinone, optionally in the presence of caesium fluoride or
tetraethylammonium fluoride, at 80-125 C for 12-18 hours, optionally in a
closed
vessel.

Scheme 5
NR
CI R\ 2
R6 N N HNR1R2 R6 N N
N N
NCI N~CI
R1502 C_Y R1502 C_Y

(V) (III)
A solution of the dichloride (V), the amine HNR'R2 and optionally an excess of
a
tertiary amine such as N-ethyldiisopropylamine, N-methylmorpholine or
triethylamine
in a suitable solvent are stirred at ambient or elevated temperature for
between 1
and 24 hours. Suitable solvents include dichloromethane, dimethylsulfoxide,
dimethylformamide, acetonitrile, tetrahydrofuran and N-methylpyrrolidinone. It
will
be appreciated that any functional groups in HNR'R2, and particularly any
primary or
secondary amine groups, may need to be protected in order to allow this
reaction to
proceed successfully. Preferably, the monochloride is treated with 3-5
equivalents
of the amine HNR'R2 and optionally 3-5 equivalents of N-ethyldiisopropylamine
in
dichloromethane, dimethylsulfoxide or a mixture of dimethylsulfoxide and N-
methylpyrrolidinone at 25-90 C for 1-18 hours.



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Alternatively, a solution of the amine HNR'R2 in a suitable solvent is treated
with
butyllithium or sodium hexamethyldisilazide at low temperature, and the
dichloride is
added to the resulting solution. Suitable solvents include tetrahydrofuran,
dioxan
and N-methylpyrrolidinone.

In certain cases, particularly when Y is a covalent bond and the amine HNR'Ra
is
only weakly nucleophilic, the direct transformation of compounds of formula
(V) into
compounds of formula (III) gives unsatisfactory results and a more indirect
alternative route may be employed. This route is described in part w) below.

f) Compounds of formula (V) can be prepared from the corresponding
pyrazolopyrimidinediones of formula (VI) as illustrated in Scheme 6.
Scheme 6
O CI
R6 N N H R6 N N
N~ N
NO N CI
R1502 C-Y H R1502C-Y

(VI) (V)
The dione is treated with a large excess of a suitable chlorinating reagent
such as
phosphorus oxychloride (POCI3) or phenylphosphonyl dichloride (PhP(O)CI2) in
the
presence of a tertiary amine such as N-ethyldiisopropylamine, N-
methylmorpholine,
triethylamine or N,N-dimethylaniline at elevated temperature for 8-48 hours.
Dimethylformamide can optionally be added as a catalyst. Alternatively, the
dione
is treated with POCI3 or PhP(O)Cl2 in a suitable solvent in the presence of a
tetraalkylammonium chloride, such as tetraethylammonium chloride, and
optionally
in the presence of a tertiary amine such as N-ethyldiisopropylamine at
elevated
temperature. Suitable solvents include acetonitrile and propionitrile.
Preferably,
the dione is treated with 10-30 equivalents of POCI3 and 3-5 equivalents of
tetraethylammonium chloride in propionitrile or acetonitrile at reflux for 4-
24 hours.


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g) Compounds of formula (VI) can be prepared from the corresponding
aminoamides of formula (VII) as. illustrated in Scheme 7.

Scheme 7
O O
R6 N N H2 R6 N N H
N No N

NH2 NO R1502C-Y R1502C-Y H

(VII) (VI)
A solution of the pyrazolecarboxamide (VII) and phosgene or an equivalent
thereof,
such as 1,1'-carbonyidiimidazole, trichloromethyl chloroformate or
bis(trichloromethyl) carbonate, in a suitable solvent is stirred at a
temperature of
between ambient temperature and the boiling point of the solvent, optionally
at
elevated pressure, for between 2 and 18 hours. Suitable solvents include
acetonitrile, dichloromethane and dimethylformamide. Preferably, a solution of
the
amine of formula (VII) and 1-2.5 equivalent of 1,1'-carbonyidiimidazole in N,N-

dimethylformamide, acetonitrile or dichloromethane is heated at between room
temperature and the reflux temperature of the reaction for 1-18 hours.

h) Compounds of formula (VII) can be prepared from the corresponding
nitroamides of formula (VIII) as illustrated in Scheme 8.

Scheme 8
O O
R N NH2 R6 N NH
N N
(NONH2
R1502C-Y R1502C-Y
(VIII) (VII)


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Reduction of the nitro group can be achieved by, for example, by transfer or
catalytic
hydrogenation, or by a dissolving metal reduction.

For transfer hydrogenation, the nitro compound is reacted with a suitable
hydrogen
donor, such as ammonium formate or cyclohexene, in a polar solvent, such as
tetrahydrofuran, methanol or ethanol, in the presence of a transition metal or
transition metal salt catalyst, such as palladium or palladium(II) hydroxide,
optionally
at elevated temperature and pressure.

For catalytic hydrogenation, a solution of the nitro compound in a polar
solvent, such
as tetrahydrofuran, methanol or ethanol, is stirred under a hydrogen
atmosphere in
the presence of a transition metal or transition metal salt catalyst, such as
palladium
or palladium(II) hydroxide, optionally at elevated pressure and temperature.
The
catalyst may be in solution (homogeneous catalysis) or in suspension
(heterogeneous catalysis).

For dissolving metal reduction, the nitro compound is treated with a suitable
reactive
metal, such as zinc or tin, in the presence of an acid such as acetic acid or
hydrochloric acid. Other reducing agents, such as tin(II) chloride, may also
be
used.

i) Compounds of formula (VIII) can be prepared from the corresponding
nitroesters of formula (IX) as illustrated in Scheme 9.


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Scheme 9
O O
R6N OCH3 R6N OH
4 _~ N
NO2 NO2
R1502C-Y R1502C-Y
(IX)

O O
R6N CI R6N NH2
N 30. N
NO2 NOa
R1502C-Y R1502C-Y
(VIII)

The methyl este r of the compounds of formula (IX) can be hydrolysed as
described
in part a) above. The acid is then converted to the corresponding acid
chloride by
treatment with oxalyl chloride and dimethylformamide in a suitable solvent
such as
dichloromethane, or with thionyl chloride. Finally, a solution of the acid
chloride in a
suitable solvent such as dichloromethane, tetrahydrofuran or dioxan is treated
with
gaseous ammonia or aqueous ammonia at between -78 C and room temperature to
provide the amide of formula (VIII).

In the embodiments (IXA) in which Y is a covalent bond and R'S is a methyl
group,
the use of one equivalent of metal hydroxide leads to the chemoselective
hydrolysis
of the ester group adjacent to the R6 substituent (Chambers, D. et al., J.
Org. Chem.
50, 4736-4738, 1985), as illustrated in scheme 9A.


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Scheme 9A
6 O
O j
R6 N OCH3 OH
N NO~ NO2
H3CO O H3CO O

(IXA)
j) Compounds of formula (IXB), wherein R6A is any group according to R6 except
hydrogen, i.e. compounds of formula (IX) except those wherein R6 is hydrogen,
can
be prepared from the corresponding esters of formula (IXc) as illustrated in
Scheme
10.

Scheme 10
O O
R6A
N OCH3 N OCH3
N I ~ N~
\
NO2 NO2
R1502C-Y R1502C-Y
(IXC) (IXB)

The compounds of formula (IXc) are treated with a combination of an alkylating
agent and a base, or with an alcohol, triphenylphosphine and a dialkyl
azodicarboxylate, as described in part c) above.

k) The compound of formula (IX') wherein R15 is methyl and Y is a covalent
bond
is described in published international patent application W000/24745 (see
preparation 2, page 48). Other compounds of formula (IX), and particularly
compounds of formula (IX ), can be prepared in two steps from the diacids of
formula (X), as illustrated in scheme 11.


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Scheme 11
O O O
6 6
R N OH N OH N OCH3
N
N02 N02
HO2C-Y HO2 C-Y R1502C'Y
(X) (XI') (IX)
In the first step, the compounds of formula (X) are treated with a nitrating
agent such
as nitric acid or a mixture of nitric acid and sulphuric acid to provide the
compounds
of formula (XI). In the second step, the two carboxylic acid groups are
esterified.
When R15 is methyl, this is conveniently achieved in a single operation. When
R'S is
other than methyl, two sub-steps are necessary, and the order in which the two
groups are esterified will depend on the nature of Y and R6. Suitable
conditions for
forming esters are well known in the art. When R15 is methyl, a preferred
method is
to treat the diacid with thionyl chloride so as to form the bis-chloride and
then react
this with methanol.

I) Certain compounds of formula (X) are commercially available or are
described in the literature, in particular those wherein Y is a covalent bond.
Compounds of formula (X) that are not items of commerce can be prepared as
illustrated in Schemes 12, 13 and 14.


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Scheme 12
O
O O O H
H2NNH2 N N OCH
OCH3 3
H3C0 y ~ \ I

(XII) Q ~-Y H
CO(XIIIA)
R6ANHNH2 3

O Q
sN
R
Rs N OCH3 N OH
N

O O
~Iy
~Iy

H3CO (XIIIB) HO (X)
The method illustrated in Scheme 12 is the Knorr pyrazole synthesis. A 1,3-
diketone of formula (XII) is reacted with hydrazine to give a pyrazole of
formula
(XIII"), or with a substituted hydrazine R6A-NHNH2, wherein R6A is as defined
in part
c) above, to give a pyrazole of formula (XIIIB).

Pyrazoles of formula (XIIIB) may also be obtained by N-alkylation of the
corresponding pyrazoles of formula (XIIIA) following the method described in
part c)
above. Hydrolysis of the ester groups as described in part a) above then
provides
the compounds of formula (X).

Compounds of formula (XII) can be prepared from the corresponding methyl
ketones
of formula (XIV) using a crossed Claisen condensation as illustrated in Scheme
13.


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Scheme 13
0 0
H3CO'kY"k
(XIV) 0 0 0
+ ~ OCH3
H3CO Y
0 0
H3C0 OCH3 (Xl 1)

0
A methyl ketone of formula (XIV) is reacted with dimethyl oxalate in a
suitable
solvent in the presence of a suitable base. Suitable solvents include ethers,
such
as tetrahydrofuran. Suitable bases include sodium hydride, potassium tert-
butoxide
and lithium diisopropylamide. Alternatively, sodium methoxide may be used as
the
base and methanol as the solvent.

Scheme 14
N/ /OCH3
~
0
+ H 0
H3COy Y N~N

I...~(~0 OliH3
O 3

(XV) ~-Y
0
OCH3 (XIIIA)
0

H3CO~Y~N2
0

(XVI)


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The method illustrated in scheme 14 is the Pechmann pyrazole synthesis. A
diazo
compound and an acetylene are combined to produce a pyrazole of formula
(XIII").
When Y is othe rthan a covalent bond two variants of the method can be
considered.
An acetylene of formula (XV) can be combined with methyl diazoacetate, or a
diazo
compound of formula (XVI) can be combined with methyl propiolate. The product
of
formula (XIIIA) may be carried forward as described above.

In addition to the methods described above, certain compounds of general
formulae
(III) and (IV) may be prepared by modification of the substituent at the C-3
position
of the pyrazolopyrimidine, as further illustrated below. It will be
appreciated that the
synthetic transformations discussed may also be used in the elaboration of
precursor compounds such as the pyrazoles of formula (IX).

m) Compounds of formula (IIIA), i.e compounds of formula (III) wherein Y is
CH2,
may be prepared from the corresponding compounds of formula (IVA), i.e.
compounds of formula (IV) wherein Y is a covalent bond, by a one-carbon
homologation method such as the Arndt-Eistert reaction illustrated in Scheme
15.

Scheme 15
R1*1 N/R2 R\N~R2
R 6 N N -,. R6N N

N )1tCl ~CI
HO2C R1502C
(IVA) (I IIA)

The carboxylic acid is converted to a reactive intermediate such as the acid
chloride
(by reaction with oxalyl chloride) or a mixed anhydride (by reaction with
isobutyl

chloroformate). The intermediate is reacted with diazomethane to provide an a-


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diazoketone. This is treated with silver oxide in the presence of R15-OH to
give the
homologated ester of formula (III").

n) Compounds of formula (IVB), i.e. compounds of formula (IV) wherein Y is
CH2,
may be prepared from the corresponding nitriles of formula (XVII) by the
method
illustrated in Scheme 16.

Scheme 16
R\N/R2 R\N~,R2
6 6
NN N NN N
N CI NCI
NC HO2C

(XVII) (IVB)
The nitrile can be hydrolysed, e.g. by treatment with aqueous mineral acids,
such as
hydrochloric acid.

o) Compounds of formula (XVII) can be prepared from the corresponding
chlorides of formula (XVIII) by the method illustrated in Scheme 17.

Scheme 17

R~N, R2 R~N, R2
R6 N N R6 N N
~
NCI NCI
CI NC
(XVI II) (XVII)


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The chloride is treated with a metal cyanide, such as sodium cyanide or
potassium
cyanide in a suitable solvent, such as dimethylsulfoxide, dimethylformamide or
ethanol.

p) Compounds of formula (XVIII) can be prepared from the corresponding
alcohols
of formula (XIX) by the method illustrated in Scheme 18.

Scheme 18
1 2 1 2
R~N, R R~N, R
R 6 N N R 6 N N
~
NCI NCI
H CI
(XIX) (XVI I I )

The alcohol is treated with a mixture of triphenylphosphine and N-
chlorosuccinimide
or tetrachloromethane, or with thionyl chloride.

q) Compounds of formula (XIX) can be prepared from the corresponding esters
of formula (IIIB), i.e. compounds according to formula (III) wherein Y is a
covalent
bond, or from the corresponding acids of formula (IVA ) by the method
illustrated in
Scheme 19.


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Scheme 19
R\N, R2
R6N N
N
i
N CI R 1 2
HO 2C N
(IVA) R6 N

N '5~~ N CI

R~ ,RZ HO
N (XIX)
R 6 N N
N
Ni CI
j
R15O2C
(IIIB)
The acids of formula (IVA) and the esters of formula (IIIB) can be reduced to
the
alcohols of formula (XIX) by treatment with lithium aluminium hydride in a
suitable
solvent at a temperature of between 00 and the boiling point of the solvent.
Suitable
solvents include ethers such as tetrahydrofuran. The acids can also be reduced
by
treatment with isobutyl chloroformate and a tertiary amine base to provide a
mixed
anhydride, followed by reaction with sodium borohydride. The esters can also
be
reduced by treatment with disobutylaluminium hydride or lithium borohydride.
r) Compounds of formula (III ), i.e. compounds of formula (III) wherein Y is
CH2CH2 can be prepared from the corresponding acrylate ester of formula (XX)
by
the method illustrated in Scheme 20.



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Scheme 20

1 2 1 2
R~N,R RN,
R
R6N ~N R 6 N N
N~ iCI N
N i
N CI
R150 C R1502C 2 (XX) (111c)

The reduction of the carbon-carbon double bond of (XX) to give the compounds
of
formula (Ilic) can be accomplished by catalytic hydrogenation using molecular
hydrogen in the presence of a transition metal catalyst such as palladium,
platinum
or nickel. When R15 is benzyl the conditions can be chosen such that only the
double bond is reduced or reduction is accompanied by hydrogenolytic cleavage
of
the ester to give the carboxylic acid.

The acrylates of formula (XX) can also be treated with alkylcopper reagents to
give
analogues of the compounds of formula (IIIc) in which an alkyl substituent is
introduced on the carbon atom adjacent to the pyrazolopyrimidine ring system,
or
with a sulphonium ylid or a carbene equivalent to give a 2-
(pyrazolopyrimidinyl)-
cyclopropane-l-carboxylate derivative.

s) Compounds of formula (XX) can be prepared from the corresponding
aidehydes of formula (XXI) by the method illustrated in Scheme 21.


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Scheme 21

1 2 R~,R2
R, N~R N

6
R6 N ~ NN N
N - C
,
NCI N CI
O
H R~502C
(XXI) (XX)
R~N~R2

R N
6 N ~
N
R ` N~CI
R1502C
(Xxzz)
The aldehyde of formula (XXI) can be converted to the acrylate ester of
formula (XX)
by reaction with a phosphorus reagent following the protocols of the Wittig,
Horner or
Wadsworth-Horner-Emmons reactions. The reagent is prepared by treating a
triphenylphosphonium salt Ph3P+CH2CO2R15.X- (Wittig), a phosphine oxide
Ph2P(O)CH2CO2R15 (Horner), or a phosphonate (EtO)2P(O)CH2CO2R15 (Wadsworth-
Horner-Emmons), with a base such as butyllithium, a lithium dialkylamide or an
alkaline metal alkoxide, in a suitable solvent such as tetrahydrofuran,
wherein X is a
suitable anion such as a halide, for example chloride, bromide or iodide.

The method is not limited to the preparation of a-unsubstituted acrylate
esters. The
use of an alkyl-substituted phosphorus reagent such as Ph3P+CH(R `)C02R15.X"
or the
equivalent phosphine oxide or phosphonate, wherein R ` is alkyl, and further
wherein
X is a suitable anion such as a halide, for example chloride, bromide or
iodide, gives
access to the corresponding a-alkyl acrylate derivative (XXZZ).


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The conversion of the aldehydes of formula (XXI) to acrylate esters of formula
(XX)
can also be achieved by reaction with a malonate derivative following the
method of
the Knoevenagel condensation.

t) Compounds of formula (XXI) can be prepared from the esters of formula
(IIIB)
or more preferably from the corresponding alcohols of formula (XIX) by the
methods
illustrated in Scheme 22.

Scheme 22

R1 NR2
R6 N N
N

>Cl 1 2
R1502C R~NR
(IIIB) N
R1 NR2 N iCI

6 013
R N N H
N (XXI)
i
N CI
HO

(XIX)

The reduction of the esters of formula (IIIB) can be achieved using
diisobutylaluminium hydride (DIBAL) in a suitable solvent at a temperature of
less
than 0 C, preferably less than -60 C. Suitable solvents include hydrocarbons
such
as pentane, hexane and toluene, ethers such as tetrahydrofuran, and mixtures
thereof.

The oxidation of the alcohols of formula (XIX) can be achieved using a
chromium(VI)
reagent such as pyridinium chlorochromate, a hypervalent iodine reagent such
as


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the Dess-Martin periodinane, or a combination of tetra-n-propylammonium
perruthenate and N-methylmorpholine-N-oxide in a suitable solvent at a
temperature
of between 0 C and ambient temperature. Suitable solvents include
dichloromethane.

u) The aldehydes of formula (XXI) may be converted to esters of formula (III")
as
illustrated in Scheme 23

Scheme 23
~ 2 R\ ,R2
R" N~R N
6
R6N N R N N
N -~ ~ ~
~
0 H
NCI H3C_S N N CI
H H3C-S\\ (~I) O (XXII)

R~N,R~
R6 N N
N
-~ i
R150 N CI
O
(IIIA)
The aldehyde is treated with methyl methylmercaptomethyl sulfoxide
(CH3SCH2S(O)CH3) and triton B in tetrahydrofuran to give intermediate (XXII)
which
is treated with the appropriate alcohol R150H and acetyl chloride to provide
the ester
of formula (IIIA). This method is particularly useful when R'5 is methyl.

v) Compounds of formula (IIIc) can also be prepared from the corresponding
chlorides of formula (XVIII) by the method illustrated in Scheme 24.


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Scheme 24
1 2
R~N,R
1 2
R11 NI~R
6
6 R N ~
RN ~N -~ N~ N
N
N CI
R1502C

N CI CI 15 (XVIII) R 02C (XXIII)

R~ 2
N,R
R6N N
N
NCI
R 02C
(IIIC)
The chloride of formula (XVIII) is reacted with a dialkyl malonate
(R1502C)2CH2 and a
5 base in a suitable solvent. Typically, the base is an alkaline metal
alkoxide such as
sodium ethoxide or potassium tert-butoxide, and the solvent is an alcohol such
as
ethanol or an ether such as tetrahydrofuran. Preferably the base and the
solvent
are chosen such as to minimise transesterification with the malonate reagent
and
the intermediate (XXIII). For example, when the reagent is diethyl malonate
the
10 base is preferably sodium ethoxide and the solvent is ethanol. The
intermediate
(XXIII) is then decarboxylated to give the product (III ). This can be
achieved by
selective hydrolysis using one equivalent of an alkaline metal hydroxide, such
as
sodium hydroxide, followed by acidification, or by any other method known in
the art.

15 The method is not limited to symmetrical malonates. For example, the use of
tert-
butyl methyl malonate would give an intermediate (XXIII) in which one R'5 is
methyl
and the other is tert-butyl. By choosing the appropriate conditions,
decarboxylation
could then be controlled to give a product (III ) in which R15 was either tert-
butyl or
methyl.



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The method can be extended to substituted malonates (R'S02C)2CHR, where R is
an
alkyl group. This gives access to compounds analogous to (IIF) in which the
group
R is a substituent on the carbon atom adjacent to the R'SO2C group. These
compounds can also be prepared by alkylating the intermediate (XXIII) with R-
Br or
R-I in the presence of an alkaline metal alkoxide base.

w) As mentioned in part e) above, the reaction of compounds of formula (VA),
i.e.
compounds of formula (V) wherein Y is a covalent bond, with weakly
nucleophilic
amines HNR'R2 is sometimes not high yielding. An alternative route is
illustrated in
Schemes 25A and 25B.

Scheme 25A

CI CI
R6 N N R6 N N
N~ N ~
N~ ~CI NCI
R O2C HO
(VA) (XXIV)

1
CI R.NR2
6
N N N R 6 N N
~ N
N CI ~ N5~CI
O O
PG
()(XV) PG (XXVI)

15 The esters of formula (VA) can be reduced to the alcohols of formula (XXIV)
according to the_methods described in part q) above. _ A preferred method is
reduction with diisobutylaluminium hydride at a temperature of between -20 C
and
0 C. The primary alcohol is then protected to give compounds of formula (XXV),
wherein PG is an alcohol protecting group. A preferred protecting group is a
trialkylsilyl group, particularly a tert-butyldimethylsilyl group. The
compounds of


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formula (XXV) are then reacted with an amine HNR'R2 according to the methods
described in part e) above to give compounds of formula (XXVI).

Scheme 25B

1 2
R~N, R R. ~R2
s N
N s
N N ~ NN N ~
N~CI ~ i
NCI
O
HO
PG (XXVI) ()(XVII)
1 2 1 2
R~N,R R~NR
6 6 30 R N N 3 ~ ~ N N N
N ~ Rs
R NN
H N R4 0R4
H
()(XVI 11) ()(XIX)
R~NR2

R6 N N
~ N
N" 'N,Rs
HO R4
0
(ID)
The compounds of formula (XXVI) are deprotected to provide the primary
alcohols of
formula (XXVII) using appropriate conditions. When PG is a trialkylsilyl group
it may
be removed by treatment with a fluoride salt, such as tetrabutylammonium
fluoride,
or with hydrochloric acid. The -NR3R4 group is then introduced according to
the
methods described in part d) above to provide compounds of formula (XXVIII).
The
primary alcohol is oxidised as described in part t) above to provide the
aldehydes of
formula (XXIX). A preferred oxidising agent is the Dess-Martin periodinane.
Finally


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the aidehydes of formula (XXIX) are oxidised to provide the acids of formula
(ID), i.e.
compounds of formula (F) wherein Y is a covalent bond. Suitable oxidising
agents
include potassium permanganate, Jones' reagent and sodium chlorite. A
preferred
method is to treat the aldehydes with sodium chlorite, sodium
dihydrogenphosphate
and 2-methyl-2-butene in tert-butanol at room temperature for about 1 hour.
Alternatively, it may be preferred to perform the oxidation of the alcohol of
formula
(XXVII) to the corresponding acid (via the corresponding aldehyde), using the
methods previously described, prior to reaction with HNR3R4, to provide the
compound of formula (ID).

x) Compounds of formula (IE), i.e. compounds of formula (I) wherein R5 is -Y-
R16
can be prepared from the corresponding monochlorides of formula (XXX) as
illustrated in Scheme 26.

Scheme 26

1 2 1 2
R`1 N,R RNI NR
R6 N N HNR3R4 R6 N

N ~ N ~ R N~CI N
N
Y Y R4
R16 R16

(XJCX) ( I E)

The monochlorides of formula (XXX) are reacted with amines HNR3R4 as described
in part d) above.


Alternatively, the -NR3R4 group may be introduced into a suitable precursor
and the
-Y-R16 group-elaborated subsequently.


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y) Compounds of formula (XXX"), i.e. compounds of formula (XXX) wherein R'6
is -CONHR1e can be prepared from the corresponding compounds of formula (IV)
as
illustrated in Scheme'27.

Scheme 27
1 2
R" ~R
R~NR 2 N
6
R N N R18-NH2 N N
N i
~ NCI
NCI O
O ~Iy
~Iy HN
HO `R1s

(IV) (XXXA)
The acid of formula (IV) is treated with the appropriate sulfonamide R18-NH2
and a
carbodiimide in a suitable solvent in the presence of 4-
(dimethylamino)pyridine. A
suitable solvent is dimethylformamide or dichloromethane. It is sometimes
preferred to introduce the R18-NH2 group in the final step, i.e. after
elaboration of the
-NR3R4 group.

Preferably, the acid is treated with 1.3 equivalents of 1-(3-
dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, 1.3 equivalents of 4-dimethylaminopyridine
and
1.2-1.3 equivalents of the sulphonamide R'eNH2, in dichloromethane at about
room
temperature for upto 18 hours.

z) Compounds of formula (XXX) wherein R'6 is a heterocyclic carboxylic
isostere
such as tetrazol-5-yl (compounds of formula (XXXB)), 5-trifluoromethyl-1,2,4-
triazol-
3-yl (compounds of formula (XXXc)) and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl
(compounds of formula (XXX )) can be prepared from compounds of formula (XXXI)
using standard methods such as those illustrated in Scheme 28A, 28B and 28C.


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Scheme 28A

1 2
R1 2 R11 N'R
6 R6 N ~
N N N M-N3 N N

CI
~ i :'
NCI N N
NC-Y N `rY
N-N
H
(XXXI) (XXXB)

The nitrile of formula (XXXI) is treated with an azide, such as an alkaline
metal azide
(M = Na, K), a trialkylsilyl azide (M = alkyl3Si) or a trialkyltin azide (M =
alkyl3Sn), in a
suitable solvent at a temperature of between ambient temperature and the
boiling
point of the solvent. A preferred azide is tributyltin azide. A preferred
solvent is
dioxan.

Scheme 28B

1 2 1 2
R~N,R R.NR
6 1. EtOH, HCI 6
R N N 2. NH3 N
N N
N ~
CI HN
NC-Y Ni \IY N CI

H2N
(XXXI)

R1 N,R2
CF3CO2Et s R NH2NH2 N N N

NCI
F3CN Y N-N

H
(XXXC)


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The nitrile of formula (XXXI) is treated with ethanol and hydrogen chloride to
form an
imidate, which is then treated with ammonia to form an amidine. The amidine is
treated with ethyl trifluoroacetate and hydrazine to provide the triazole of
formula
(XXX ). The 5-(methylsulfonyl)-substituted triazole can be prepared in an

analogous manner.
Scheme 28C

1 2 1 R 2
R\N,R R, N

R N --- N N H20 H R N N
N /~ - N
-\ CI HO~N
NC-Y N Y N CI
H2N
(XXXI)
R\NR2
CDI R N N
N
~
O N N CI
O-N
H
(XXXD)
The nitrile of,formula (XXXI) is treated with hydroxylamine to form an N-
hydroxyamidine, which is then treated with 1,1'-carbonyldiimidazole to provide
the
oxadiazolone of formula (XXX').

aa) Compounds of formula (XXXI) can be prepared using the methods described
in part o) above,--or from compounds of formula (IV) using the method
illustrated in
Scheme 29.


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Scheme 29

R 1 2 1 2
~NR R\NR
6

R~N N ~ Rs N --- N
% N
HO N CI NCI
~Iy H2N
~-Y
O O
(IV)

R" N~R2
R6 / N N
~
N CI
NC-Y

(XXXI)
The acid of formula (IV) is converted into the corresponding primary amide
following
the method described in part i) above. The amide is then dehydrated using
trifluoroacetic anhydride.

bb) Compounds of formula (III) or (XXXI) wherein Y is -CH2 O-CH2 may be
prepared from the alcohols of formula (XIX) by alkylation with an alkyl a-
haloacetate
or an a-haloacetonitrile derivative, as illustrated in scheme 29.


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Scheme 30

1 2
R1 ~R2 R~N,R
N 6 HaI-CH2CO2RA R6 N ~
N
N N~

i N~CI
NCI
O
HO (XIX) RA02C

Hal-CH2CN
R~N,R2
R6 N ~ N
N
i
N CI
O

NCJ
Hal is chlorine, bromine or iodine, preferably chlorine or bromine. The
alcohol
(XIX) and alkylating agent are combined in a suitable solvent in the presence
of a
base such as potassium carbonate or sodium hydride. Suitable solvents include
tetrahydrofuran and dimethylformamide. '

It will be appreciated by those skilled in the art that certain compounds of
formula (I)
may undergo standard chemical transformations to provide alternative compounds
of formula (I), for example the preparation of example 184, by dealkylation of
an
alkyl ether.
For some of the steps of the here above described process of preparation of
the
compounds of formula (I), it may be,necessary to protect potential reactive
functions
that are not wished to react, and to cleave said protecting groups in
consequence. In
such a case, any compatible protecting radical can be used. In particular
rriethods of
protection and deprotection such as those described by T.W. GREENE (Protective
Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P.
J.
Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.


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The following compounds form further aspects of the present invention:

A compound of formula (III)

R~N~R2
R 6 N N
N
5~
CI
RAO2C-Y

(III)
wherein R', R2 , R6 , R" and Y are as defined above.
Preferred is a compound of formula (III )

1 2
R6 R~NR
N N
N~ ~
N CI
RA02C-Y

(III )
wherein R1, R2, R6 , R" and Y are as defined above.
A compound of formula (V)

CI
R 6 N N
NJ
NCI
RA02C-Y

(V)
wherein R6, RA and Y are as defined above.


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Preferred is a compound of formula (VB)

R6 CI
N N
N\ I
N CI
RA02C-Y

(VB)
wherein R6, R" and Y are as defined above.

The invention is further illustrated by the following, non-limiting examples.
Melting points were determined on a Gallenkamp melting point apparatus using
glass capillary tubes and are uncorrected. Unless otherwise indicated all
reactions
were carried out under a nitrogen atmosphere, using commercially available
anhydrous solvents. `0.88 Ammonia' refers to commercially-available aqueous
ammonia solution of about 0.88 specific gravity. Thin-layer chromatography was
performed on glass-backed pre-coated Merck silica gel (60 F254) plates, and
silica

gel column chromatography was carried out using 40-63,um silica gel (Merck
silica
gel 60). Ion exchange chromatography was performed using with the specified
ion
exchange resin which had been pre-washed with deionised water. Proton NMR
spectra were measured on a Varian Inova 300, Varian Inova 400, or Varian
Mercury
400 spectrometer in the solvents specified. In the NMR spectra, only non-
exchangeable protons which appeared distinct from the solvent peaks are
reported.
Low resolution mass spectra were recorded on either a Fisons Trio 1000, using
thermospray positive ionisation, or a Finnigan Navigator, using electrospray
positive
or negative ionisation. High resolution mass spectra were recorded on a Bruker
Apex II FT-MS using electrospray positive ionisation. Combustion analyses were
conducted by Exeter Analytical UK. Ltd., Uxbridge, Middlesex. Optical
rotations
were determined at 25 C using a Perkin Elmer 341 polarimeter using the
solvents


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and concentrations specified. Example compounds designated as (+) or (-)
optical
isomers are assigned based on the sign of optical rotation when determined in
a
suitable solvent.

Abbreviations, Definitions and Glossary
AcOH acetic acid
Amberlyst 15 Ion exchange resin, available from Aldrich Chemical Company
APCI Atmospheric Pressure Chemical Ionisation
ArbocelTM Filtration agent, from J. Rettenmaier & Sohne, Germany
atm Pressure in atmospheres (1 atm = 760 Torr = 101.3 kPa)
BiotageTM Chromatography performed using Flash 75 silica gel cartridge,
from Biotage, UK
BOC tert-butoxycarbonyl
br Broad
c Concentration used for optical rotation measurements in g per
100 ml (1 mg/mI is c 0.10)
cat Catalytic
CBz benzyloxycarbonyl
CDI N,N'-carbonyldiimidazole
d Doublet
DCC N,N'-dicyclohexylcarbodiimide
DCM dichloromethane
dd Doublet of doublets
DEAD diethyl azodicarboxylate
Degussa 101 10 wt% palladium on activated carbon, Degussa type E101
available from Aldrich Chemical Company
Dess-Martin 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1 H)-one
periodinane
Develosil Supplied by Phenomenex - manufactured by Nomura Chemical
Combi-RP C30 Co. Composed of spherical silica particles ( size 3 pm or 5 pm)


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hplc column which have a chemically bonded surface of C30 chains. These
particles are packed into stainless steel columns of dimensions 2
cm internal diameter and 25 cm long.
DIAD diisopropyl azodicarboxylate
DIBAL diisobutylaluminium hydride
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethyl sulphoxide
Dowex Ion exchange resin, from Aldrich Chemical Company
ee Enantiomeric excess
Et3N triethylamine
EtOAc ethyl acetate
EtOH ethanol
HOAT 1-hydroxy-7-azabenzotriazole
HOBT 1-hydroxybenzotriazole hydrate
HRMS High Resolution Mass Spectrocopy (electrospray ionisation
positive scan)'
Hunig's base N-ethyidiisopropylamine
HyfloTM Hyflo supercel , from Aldrich Chemical Company
KHMDS potassium bis(trimethylsilyl)amide

liq Liquid
LRMS Low Resolution Mass Spectroscopy (electrospray or thermospray
ionisation positive scan)
LRMS (ES-) Low Resolution Mass Spectroscopy (electrospray ionisation
negative scan)
m Multiplet
m/z Mass spectrum peak
MCITM gel High porous polymer, CHP20P 75-150 m, from Mitsubishi
Chemical Corporation

MeOH methanol
Mukaiyama's 2-chloro-l-methylpyridinium iodide


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reagent
NaHMDS sodium bis(trimethylsilyl)amide
NMM N-methylmorpholine
NMO 4-methylmorpholine N-oxide
NMP 1 -methyl-2-pyrrol id i none
Phenomenex Supplied by Phenomenex. Composed of spherical silica particles
Luna C18 hplc (size 5 pm or 10 pm) which have a chemically bonded surface of
column C18 chains. These particles are packed into a stainless steel
column of dimensions 2.1cm internal diameter and 25 cm long.
psi Pounds per square inch (1 psi = 6.9 kPa)
PyBOPO Benzotriazol-1 -yloxytris(pyrrolidino)phosphonium
hexafluorophosphate
PyBrOPO bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
q Quartet
Rf Retention factor on TLC
s Singlet
Sep-Pak Reverse phase C,8 silica gel cartridge, Waters Corporation
t Triplet
TBDMS-Cl tert-butyidimethyichlorosilane
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC Thin Layer Chromatography
TMS-Cl chlorotrimethylsilane
WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
8 Chemical shift

The following Examples illustrate the preparation of the compounds of the
formula
(I):-



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Preparation 1
tert-Butyl (3R)-3-methoxypyrrolidine-1-carboxylate
0 CH3
H3C J~ CH3
O O CH3

tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (12.5g, 66.70mmol) was
dissolved
in tetrahydrofuran (334mL) and the reaction mixture cooled to 0 C in an ice
bath.
The reaction mixture was treated with 80% sodium hydride in mineral oil
(2.20g,
73.3mmol) and stirred until back at room temperature. The reaction mixture was
then treated with methyl iodide (14.5g, 100.Ommol) and stirred at room
temperature
for 18 hours. The reaction mixture was diluted with water (100mL) and
concentrated
in vacuo until just the aqueous remained. The aqueous solution was treated
with
ethyl acetate (750mL), the organic layer separated, dried over magnesium
sulphate
and concentrated in vacuo to yield the title product as a brown oil, 12.48g.

'H NMR (CDCI3, 400MHz) b: 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m,
4H),
3.86 (m, 1 H)

Preparation 2
tert-Butyl (3S)-3-methoxypyrrolidine-l-carboxylate
O CH3
H3C AH3
O .,,. O CH3

The title product was prepared by a method similar to that described for
preparation
1 using tert-butyl (3S)-3-hydroxypyrrolidine-l-carboxylate.

'H NMR (CDCI3, 400MHz) 8: 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m,
4H),
3.86 (m, 1 H)


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Preparation 3
(3R)-3-Methoxy-pyrrolidine hydrochloride
~+o 0 NH HCI
H3li

Hydrogen chloride gas was bubbled through an ice-cooled solution of the
compound
from preparation 1(6.02g, 30.Ommol) in dichloromethane (30mL), and the
reaction
then allowed to warm to room temperature and stirred for 48 hours. The
solution was
concentrated under reduced pressure and the residue triturated with ether. The
resulting crystals were filtered off and dried in vacuo to afford the title
compound.

'H NMR (CD3OD, 400MHz) b: 2.06 (m, 1 H), 2.20 (m, 1 H), 3.26-3.42 (m, 7H),
4.17
(m, 1 H).

Preparation 4
(3S)-3-Methoxy-pyrrolidine hydrochloride
' O"" NH HCI
H3C
The title compound was obtained from the compound from preparation 2,
following a
similar method to that described in preparation 3.
'H NMR (CD3OD, 400MHz) 8: 2.14 (m, 1 H), 2.20 (m, 1 H), 3.24-3.44 (m, 7H),
4.18
(m, 1 H).

Preparation 5
2-Chloropyrimidin-4-ylamine
H2N N\ /CI
N

2,4-Dichloropyrimidine (625mg, 4.23mmol) was dissolved in n-butanol (3mL) and
the
solution treated with ammonia (620 L). The reaction mixture was heated to 100
C
for 20 minutes before being allowed to cool to room temperature. Methanol was
added to help dissolved the precipitate formed on cooling and the solution was


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concentrated in vacuo. The residue was purified by column chromatography on
silica
gel eluting with dichloromethane:methanol 100:0 to 96:4.

'H NMR (CD3OD, 400MHz) S: 6.41 (d, 1 H), 7.90 (d, 1 H)
Preparation 6
2-Methoxypyrimidin-4-ylamine

H2N N~O.CH
3
~ N

The chloro compound of preparation 5(1.52g, 11.8mmol) was dissolved in
methanol
(17mL) and the solution treated with a 4.62M solution of sodium methoxide in
methanol (2.8mL, 12.9mmol). The reaction mixture was then refluxed under
nitrogen
for 6 hours. The reaction mixture was filtered whilst hot and concentrated in
vacuo to
a volume of 2mL and the solid allowed to crystallise out. The crude product
was
recrystallised from methanol and dried in an oven to yield the title product,
390mg.
'H NMR (DMSO-D6, 400MHz) b: 3.75 (s, 3H), 6.05 (d, 1 H), 6.80 (m, 2H), 7.80
(d, 1 H)
Preparation 7
Dimethyl 4-nitro-1-(2-propoxyethyl)-1 H-pyrazole-3,5-dicarboxylate
H3C,,,,,--"0
O
<OCH3
0 NO2
H3C O

Dimethyl 4-nitro-1 H-pyrazole-3,5-dicarboxylate (W000/24745, page 48,
preparation
2) (15g, 60mmol), 2-propoxyethanol (8.2mL, 70mmol) and triphenylphosphine
(18.9g, 70mmol) were dissolved in tetrahydrofuran (150mL) and the solution
cooled
to 0 C. The solution was treated with diisopropyl azodicarboxylate (14.2mL,
70mmol) and the reaction mixture stirred at 0 C for 3 hours before being
allowed to
warm to room temperature. The reaction mixture was concentrated in vacuo and
the
residue purified by column chromatography on silica gel eluting with ethyl


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acetate:pentane 15:85 and then again eluting with dichloromethane to yield the
title
product.
'H NMR (CD3OD, 400MHz) 8: 0.82 (t, 3H), 1.47 (q, 2H), 3.34 (t, 2H), 3.78 (t,
2H),
3.91 (s, 6H), 4.76 (t, 2H). MS APCI+ m/z 316 [MH]+

Preparation 8
Dimethyl (2'R)-1-(2'-methox propyl)-4-nitro-1H-pyrazole-3,5-dicarboxylate
O~CH3
H3C O~ICH3
,N
N~

O NO2
H3C

The title compound was prepared by a method similar to that described for
preparation 7 using (2R)-2-methoxypropanol (Chem. Eur. J., 1997, 3 (12), 2063-
2070). The title product was purified by column chromatography on silica gel
eluting
with pentane:dichloromethane 20:80.
'H NMR (CDCI3, 400MHz) 5: 1.18 (d, 3H), 3.20 (s, 3H), 3.70 (m, 1 H), 3.92 (s,
3H),
3.94 (s, 3H), 4.42 (m, 1 H), 4.74 (m, 1 H). MS APCI+ m/z 302 [MH]+

Preparation 9
Dimethyl 1-(2-isopropoxyethyl)-4-nitro-1 H-pyrazole-3,5-dicarboxylate
CH3
H3C O"'-1 O,CH3
,N
N~

O NO2
H3C O

Dimethyl 4-nitro-1 H-pyrazole-3,5-dicarboxylate (11.4g, 50mmol) was dissolved
in
tetrahydrofuran (200mL) and the solution treated with triphenylphosphine
(14.4g,
55mmol) and 2-isopropoxyethanol (6.36mL, 55mmol). The mixture was cooled on an


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ice bath to 0 C and diisopropyl azodicarboxylate (10.8mL, 55mmol) added
dropwise
over 10 minutes, keeping the temperature between 20 C and 30 C. The reaction
mixture was then stirred at room temperature for 30 minutes. The reaction
mixture
was concentrated in vacuo and the crude product azeotroped with
dichloromethane
to yield the title product.
'H NMR (CDC13, 400MHz) 8: 1.02 (d, 6H), 3.45 (m, 1 H), 3.72 (t, 2H), 3.90 (s,
3H),
3.94 (s, 3H), 4.74 (t, 2H). MS ES+ m/z 216 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 9, using the appropriate RsOH
alcohol.
R6 O,CH3
I
,N
N~ ~ O
/0 NO2
H3C O

No R6 Data
'H NMR (CDC13, 400MHz) 8: 1.10 (d, 3H),
10 -(CH02CH(CH3)OCH3 2.00 (m, 2H), 3.20 (s, 3H), 3.30 (m, 1 H), 3.86
(m, 6H), 4.62 (m, 2H)

'H NMR (CDC13, 400MHz) S: 0.11 (m, 2H),
~O1-'-1 CH 0.48 (m, 2H), 0:92 (m, 1 H), 3.22 (d, 2H), 3.90
11 2
(m, 2H), 3.97 (m, 6H), 4.81 (m, 2H). MS ES+
m/z 350 [MNa]+

O 'H NMR (CDC13, 400MHz) 8: 1.47 (m, 2H),
12 1.86 (m, 2H), 2.24 (m, 1 H), 3.36 (m, 2H),
CH2 3.74 (m, 2H), 3.93 (s, 3H), 3.97 (s, 3H), 4.52

(d, 2H). MS ES+ m/z 328 [MH]+


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'H NMR (CDCI3, 400MHz) S: 1.50 (m, 4H),

13 aCH 1. 84 (m, 2H), 3.27 (m, 1 H), 3.60-3.90 (m,
2 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.45 (m, 1 H),
4.73 (m, 1 H). MS APCI+ m/z 328 [MH]+

= Preparation 11 was prepared using 2-(cyclopropylmethoxy)ethanol (FR
2248255, Pg. 2, example 1) as the R6OH alcohol.

= Preparation 12 was prepared using tetrahydro-2H-pyran-4-methanol (DE
4233431, Pg. 4, example 1) as the R6OH alcohol.

Preparation 14
Dimethyl 1-(2-ethoxyethyl)-4-nitro-1 H-pyrazole-3,5-dicarbox I~
H3CO") OIICH3
N
N~ / O
O NO2
H3C O

Dimethyl 4-nitro-1 H-pyrazole-3,5-dicarboxylate (2.0g, 8.83mmol) was added to
a
solution of 2-ethoxyethyl bromide (1.18mL, 10.45mmol) and potassium carbonate
(1.32g, 9.56mmol) in N,N-dimethylformamide (35mL) and the reaction mixture
stirred
for 48 hours at room temperature. The reaction mixture was concentrated in
vacuo
and the residue partitioned between ethyl acetate (200mL) and water (100mL).
The
organic layer was separated, dried over magnesium sulphate and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel
eluting with pentane:ethyl acetate 100:0 to 70:30 to yield the title product,
1.63g.
'H NMR (CDCI3, 400MHz) 8: 1.07 (s, 3H), 3.41 (q, 2H), 3.73 (t, 2H), 3.89 (s,
3H),
3.94 (s, 3H), 4.76 (t, 2H). MS APCI+ m/z 302, [MH]+



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Preparation 15
Dimethyl 1-[2-(2-methoxYethoxy)ethyI]-4-nitro-1 H-pyrazole-3,5-dicarboxylate

H3c~ o,CH3
,N
O

O N 02
H3C 0

Dimethyl 4-nitro-1 H-pyrazole-3,5-dicarboxylate (9.53g, 41.6mmol) and
potassium
carbonate (3.44g, 25mmol) were dissolved in N,N-dimethylformamide (140mL)
under nitrogen. The mixture was then treated with a solution of 1-bromo-2-(2-
methoxyethoxy)ethane (9.90g, 54mmol) in N,N-dimethylformamide (10mL). The
reaction mixture was stirred at 30 C for 18 hours and then allowed to cool to
room
temperature. Additional 1-bromo-2-(2-methoxyethoxy)ethane (9.90g, 54mmol) and
potassium carbonate (3.44g, 25mmol) were added and the reaction mixture
allowed
to stir at 30 C for 4 hours. The reaction mixture was concentrated in vacuo
and the
residue taken up in ethyl acetate (200mL) and water (200mL). The aqueous was
separated and washed with ethyl acetate (200mL), the organics were combined
and
washed with water. The organic layer was dried over magnesium sulphate and
concentrated in vacuo to yield the title product.

'H NMR (CDCI3, 400MHz) 8: 3.25 (s, 3H), 3.38 (m, 2H), 3.50 (m, 2H), 3.80 (t,
2H),
3.92 (s, 3H), 3.93 (s, 3H), 4.77 (t, 2H). MS APCI+ mlz 333 [MH]+

Preparation 16
Dimethyl 1-(2-methoxyethyl)-4-nitro-1 H-pyrazole-3,5-dicarboxylate
H3CI. 0"') 0,CH3
,N
N~ O
/0 NO2
H3C O

The title compound was prepared by a method similar to that described for
preparation 15 using 1-bromo-2-methoxyethane.


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'H NMR (CDCI3, 400MHz) 8: 3.22 (s, 3H), 3.67 (m, 2H), 3.89 (m, 6H), 4.77 (m,
2H)
MS ES+ m/z 288 [MH]+

Preparation 17
4-Nitro-l-L2-propoxyeth rl -1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester
O
~N
N\ ~ OH
O NO2
H3C O

The ester of preparation 7(150mg, 0.5mmol) and potassium hydroxide (29mg,
0.55mmol) were dissolved in methanol (2mL) and the reaction mixture stirred at
room temperature for 48 hours. The reaction mixture was concentrated in vacuo
and
the residue taken up in water. The aqueous was washed with ether (x2) and
extracted with dichloromethane. The organic phase was then washed with 2M
hydrochloric acid (x2) and water (x2), dried over magnesium sulphate and
concentrated in vacuo to yield the title product.
'H NMR (CD3OD, 400MHz) 8: 0.83 (t, 3H), 1.49 (q, 2H), 3.36 (t, 2H), 3.80 (t,
2H),
3.90 (s, 3H), 4.78 (t, 2H). MS APCI+ m/z 302 [MH]+

Preparation 18
4-Nitro-1-(2-ethoxyethyl)-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester
H3CO"-j OH
,N
N~ O
O NO2
H3C O

The ester of preparation 14 (1.63g, 5.4mmol) was added to a solution of
potassium
hydroxide (330mg, 5.9mmol) in methanol (20mL) and the reaction mixture stirred
at
room temperature for 18 hours. The reaction mixture was concentrated in vacuo
and
the crude product dissolved in water and washed with ether. The aqueous phase


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was acidified with 2M hydrochloric acid and extracted into dichloromethane
(3x100mL). The organics were combined, dried over magnesium sulphate and
concentrated in vacuo to yield the title product.

'H NMR (CD3OD, 400MHz) 8: 1.07 (s, 3H), 3.47 (q, 2H), 3.80 (t, 2H), 3.88 (s,
3H),
4.77 (t, 2H). MS APCI+ m/z 288 [MH]+

Preparation 19
1-(2-Isopropoxyethyl)-4-nitro-1 H-pyrazole-3,5-dicarboxylic acid 3-methyl
ester
Cj'H3

H3C/I\O"~) OH
,N
N~ O

/0 NO2
H3C O

The ester of preparation 9 (15.8g, 50mmol) was dissolved in methanol (200mL)
and
the solution cooled in an ice bath before being treated with potassium
hydroxide
(2.8g, 50mmol). The reaction mixture was then stirred at room temperature for
18
hours. The reaction mixture was concentrated in vacuo and the residue
partitioned
between dichloromethane (500mL) and water (250mL). The aqueous phase was
separated, acidified with hydrochloric acid and then extracted with
dichloromethane
(2x500mL). The combined dichloromethane extracts were dried over magnesium
sulphate and concentrated in vacuo'to yield the title product as a white
solid, 11.4g.
'H NMR (DMSO-D6, 400MHz) 8: 0.92 (d, 6H), 3.45 (m, 1 H), 3.67 (t, 2H), 3.82
(s,
3H), 4.66 (t, 2H). MS ES+ m/z 302 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 19 using the appropriate
ester of
preparations 8, 10, 11, 13, 15 and 16


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R6 OH
i
,N
N~ O

/ 0 N02
H3C O

No R6 Data

'H NMR (DMSO-D6, 400MHz) b: 1.02 (d, 3H),
20 -(CH2)2CH(CH3)OCH3 1.90 (m, 2H), 3.18 (s, 3H), 3.28 (m, 3H), 3.37 (m,
1 H), 4.58 (m, 2H).

'H NMR (CDCI3, 400MHz) 8: 3.30 (s, 3H), 3.50
21 -(CH2)2O(CH2)20CH3 (m, 2H), 3.58 (m, 2H), 3.90 (m, 5H), 4.80 (t, 2H).
MS APCI+ m/z 318 [MH]+

CH3 'H NMR (DMSO-D6, 400MHz) b: 1.05 (d, 3H),
22 H3C,, 0 " ~CH2 3.14 (s, 3H), 3.72 (m, 1 H), 3.84 (s, 3H), 4.48 (m,
1 H), 4.60 (m, 1 H). MS APCI+ m/z 288 [MH]+

'H NMR (CDC13, 400MHz) b: 0.12 (m, 2H), 0.48
23 0 CH2 (m, 2H), 0.95 (m, 1 H), 3.32 (d, 2H), 3.91 (m, 5H),
4.83 (t, 2H). MS ES- m/z 312 [M-H]-

'H NMR (DMSO-D6, 400MHz) b: 3.22 (s, 3H),
24 -(CH2)20CH3 3.71 (m, 2H), 3.83 (s, 3H), 4.77 (m, 2H), 9.95 (m,
1 H). MS ES+ m/z 274 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 1.19 (m, 1 H),
O 1.36 (m, 3H), 1.58 (m, 1 H), 1.73 (m, I H), 3.22
25 CH2 (m, 1 H), 3.66 (m, 1 H), 3.75 (m, 1 H), 3.80 (s, 3H),
4.47 (m, 1 H), 4.60 (m, 1 H). MS APCI+ m/z 314
[MH]+


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Preparation 26
4-Nitro-1-(tetrahydropyran-4-ylmethyl)-1 H-pyrazole-3,5-dicarboxylic acid 3-
methyl
ester
O

OH
,N
N~ O
4 N02
H3C O

The ester of preparation 12 (13.7g, 42mmol) was added to a solution of
potassium
hydroxide (2.59g, 46.2mmol) in methanol (200mL) and the reaction mixture
stirred at
room temperature for 18 hours. The reaction mixture was concentrated in vacuo
and
the residue partitioned between dichloromethane (300mL) and water (200mL). The
dichloromethane layer was concentrated in vacuo and the residue partitioned
between ether (200mL) and water (200mL). The aqueous was added to the first
aqueous extract, washed with ether (2x200mL) and acidified with hydrochloric
acid.
The solution was extracted with dichloromethane (3x400mL), dried over
magnesium
sulphate and concentrated in vacuo to yield the title product.

'H NMR (DMSO-D6, 400MHz) 8: 1.24 (m, 2H), 1.36 (m, 2H), 2.10 (m, 1 H), 3.20
(m,
2H), 3.78 (m, 2H), 3.84 (s, 3H), 4.43 (d, 2H),
MS APCI+ m/z 314 [MH]+

Preparation 27
Methyl 5-carbamoyl-4-nitro-l-(2-propoxyethyl)-1 H-pyrazole-3-carboxylate
H3C,,/-,O-'^') O
,N
N\ / NH2
0 NO2
H3C O
The carboxylic acid of preparation 17 (13.2g, 44mmol) was dissolved in
dichloromethane (140mL) and the solution treated with N,N-dimethylformamide


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(150 L). The mixture was cooled in an ice bath with acetone to -5 C and oxalyl
chloride (11.48mL, 132mmol) added dropwise over 30 minutes. The reaction
mixture
was stirred at -5 C for 1 hour and then allowed to warm to room temperature
and
stirred for a further 90 minutes. The reaction mixture was concentrated in
vacuo and
the residue azeotroped with dichloromethane (x2). The crude product was
dissolved
in tetrahydrofuran and cooled in an ice bath. 0.88 Ammonia (60mL) was added to
the reaction mixture over 10 minutes, the ice bath removed and the reaction
mixture
stirred for 1 hour until at room temperature. The reaction mixture was
concentrated
in vacuo and the residue taken up in water. The precipitate formed was
filtered off

and dried for 18 hours in an oven at 70 C to yield the title product, 10.22g.

'H NMR (DMSO-D6, 400MHz) S: 0.81 (t, 3H), 1.45 (q, 2H), 3.32 (t, 2H), 3.74 (t,
2H),
3.90 (s, 3H), 4.40 (t, 2H), 8.33 (s, 1 H), 8.48 (s, 1 H)

Preparation 28
Methyl 5-carbamoyl-1 -(2-methoxyethyl)-4-nitro-1 H-pyrazole-3-carboxylate
H3C~- 0")

~N
N / NH2
O N02
O-CH3
The title compound was prepared by a method similar to that described for
preparation 27 using the carboxylic acid of preparation 24.

'H NMR (DMSO-D6, 400MHz) 8: 3.18 (s, 3H), 3.65 (m, 2H), 4.82 (s, 3H), 4.38 (m,
2H), 8.33 (m, I H), 8.47 (m, 1 H). MS ES+ m/z 273 [MH]+


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Preparation 29
Methyl 5-carbamo rLl-1-(2-ethoxyethrl -4-nitro-1 H-pyrazole-3-carboxylate
H3C O NH2
,N
O
/ 0 N O2
H3C O

Oxalyl chloride (1.2mL, 13.76mmol) and N,N-dimethylformamide (39 L) were added
to a solution of the carboxylic acid of preparation 18 (1.33g, 4.63mmol) in
dichloromethane (20mL) and the reaction mixture stirred at room temperature
for 2
hours. The reaction mixture was concentrated in vacuo and azeotroped from
dichloromethane (3x5OmL). The product was dissolved in tetrahydrofuran (50mL),
cooled in an ice bath, treated with 0.88 ammonia solution (10mL) and stirred
for 18
hours at room temperature. The mixture was concentrated in vacuo and the
residue
partitioned between dichloromethane (200mL) and water (50mL). The organics
phase was dried over magnesium sulphate and concentrated in vacuo to yield the
title product.

'H NMR (DMSO-D6, 400MHz) S: 1.06 (t, 3H), 2.48 (m, 2H), 3.77 (m, 2H), 3.84 (s,
3H), 4.38 (m, 2H), 8.35 (m, 1 H), 8.46 (m, 1 H). MS APCI+ m/z 287 [MH]+
Preparation 30
Methyl 5-carbamoyl-1-[2-(2-methoxy-ethoxy)-ethLl]-4-nitro-1 H-pyrazole-3-
carboxylate

ro
H3C~0 NH2
,N
N~ ~ O
, NO2
H3C O
The title product was prepared by a method similar to that described for
preparation
29 using the carboxylic acid of preparation 21.


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'H NMR (CDCI3, 400MHz) 8: 3.30 (s, 3H), 3.50 (m, 2H), 3.58 (m, 2H), 3.90 (m,
2H),
3.99 (s, 3H), 4.50 (t, 2H), 6.25 (m, 1 H), 7.80 (m, 1 H). MS APCI+ m/z 317
[MH]+

Preparation 31
Methyl 5-carbamoyl-1-(2-cyclopropyImethoxy-ethyl)-4-nitro-1 H-pyrazole-3-
carbox rLlate

O

NH2
N~ ~ 0
O Np2
H3C p

The title compound was prepared by a method similar to that described for
preparation 29 using the carboxylic acid of preparation 23.

'H NMR (CDC13, 400MHz) 6: 0.12 (m, 2H), 0.52 (m, 2H), 0.95 (m, 1 H), 3.27 (m,
2H),
3.87 (t, 2H), 3.96 (s, 3H), 4.61 (t, 2H), 6.09 (m, 1 H), 7.72 (m, 1 H)
MS ES+ m/z 335 [MNa]+

Preparation 32

Methyl 5-carbamoyl-l-(2-isopropoxyethyl)-4-nitro-1 H-pyrazole-3-carboxylate
3

H3C/\O~ NH2
,N
N~ ~ 0

O Np2
H3C

The carboxylic acid of preparation 19 (11.9, 37.8mmol) was dissolved in
dichloromethane (140mL) and the solution treated with oxalyl chloride_(4.OmL,
45.4mmol) and N,N-dimethylformamide (310 L, 4mmol). The reaction mixture was
stirred at room temperature for 18 hours, then concentrated in vacuo and the
residue azeotroped with dichloromethane (2x100mL). The product was dissolved
in


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tetrahydrofuran (200mL) and the solution cooled in an ice-bath and then
treated with
0.88 ammonia (50mL). The reaction mixture was stirred for 15 minutes before
being
concentrated in vacuo and partitioned between dichloromethane (1000mL) and
water (500mL). The aqueous was separated and extracted with dichloromethane
(3x300mL), the organics were combined, dried over magnesium sulphate and
concentrated in vacuo to yield the title product, 10.4g.

'H NMR (DMSO-D6, 400MHz) 8: 0.95 (d, 6H), 3.44 (m, 1 H), 3.68 (t, 2H), 3.83
(s, 3H),
4.66 (t, 2H). MS APCI+ m/z 301 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 32, using the appropriate
carboxylic
acid of preparations 20 and 22.

R NH2
N
N~ I O
/0 NO2
H3C O

No R6 Data

'H NMR (CDCI3, 400MHz) 8: 1.16 (d, 3H), 2.08
33 -(CH2)2CH(CH3)OCH3 (m, 2H), 3.25 (s, 3H), 3.38 (m, 1 H), 3.97 (s,
3H), 4.59 (t, 2H). MS ES- m/z 299 [M-H]-

CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.08 (d, 3H),
34 H3C" 0 3.04 (s, 3H), 3.73 (m, 1 H), 3.84 (s, 3H), 4.25
~~ CH 2 (m, 2H), 8.30 (s, 1 H), 8.48 (s, 1 H). MS ES+
m/z 309 [MNa]+


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Preparation 35
Methyl 5-carbamoyl-4-nitro-l-(tetrahydropyran-4- I~methLrl)-1 H-pyrazole-3-
carboxylate
O

NH2
,N
N~ O
4 N02
H3C O

The carboxylic acid of preparation 26 (11.3g, 36mmol) was dissolved in
dichloromethane (150mL) and the solution treated with oxalyl chloride (38mL,
43.2mmol) and N,N-dimethylformamide (280 L, 3.6mmol). The reaction mixture was
stirred at room temperature for 18 hours and then concentrated in vacuo. The
residue was azeotroped from dichloromethane (2x200mL) and the resulting solid

dissolved in tetrahydrofuran and cooled to -30 C. The solution was treated
with 0.88
ammonia (3.85mL, 79.2mmol) and stirred at -30 C for 1 hour. The reaction
mixture
was concentrated in vacuo, diluted with water (100mL) and extracted with ethyl
acetate (2x400mL). The combined organics were dried over magnesium sulphate
and concentrated in vacuo. The residue was triturated with methanol and ether
and
dried in vacuo to yield the title product.

'H NMR (DMSO-D6, 400MHz) S: 1.20 (m, 2H), 1.40 (m, 2H), 2'.10 (m, 1 H), 3.22
(m,
2H), 3.81 (m, 2H), 3.86 (s, 3H), 4.19 (d, 2H), 8.37 (m, 1 H), 8.53 (m, 1 H),
MS APCI+ m/z 313 [MH]+


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Preparation 36
Methyl 5-carbamoyl-4-nitro-l-(tetrahyd ropyran-2-yimethyl)-1 H-pyrazole-3-
carboxylate
0

NH2
N
N~ O
O N02
H3C O

The title compound was prepared by a method similar to that described for
preparation 35 using the carboxylic acid of preparation 25.
'H NMR (DMSO-D6, 400MHz) 8: 1.18 (m, 1 H), 1.40 (m, 3H), 1.58 (m, 1 H), 1.78
(m,
1 H), 3.22 (m, 1 H), 3.65 (m, 1 H), 3.78 (m, 1 H), 3.85 (s, 3H), 4.22 (m, 2H),
8.27 (m,
1 H), 8.46 (m, 1 H). MS APCI+ m/z 313 [MH]+

Preparation 37
Methyl 4-amino-5-carbamoyl-1-(2-propoxyethyl)-1 H-pyrazole-3-carboxylate
,,,,-\O-'~) O
H3C0
,N
NH2
/ 0 NH2
H3C 0

The nitro compound of preparation 27 (10g, 33mmol) was dissolved in ethanol
(180mL) and the solution treated with palladium(II) hydroxide (933mg, 6.7mmol)
and`
heated to 75 C. Ammonium formate (21 g, 330mmol) was added and the reaction
mixture was stirred at 75 C for 3 hours. The reaction mixture was filtered
through
Arbocel under nitrogen washing through with ethanol. The filtrate was
concentrated in vacuo to yield the title product as a pale pink solid, 9.1g.

'H NMR (CD3OD, 400MHz) 8: 0.84 (t, 3H), 1.51 (q, 2H), 3.40 (t, 2H), 3.83 (t,
2H),
3,.89 (s, 3H), 4.56 (t, 2H). MS APCI+ m/z 271 [MH]+


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Preparation 38
Methyl 4-amino-5-carbamoyl-1-(2-ethoxyethyl)-1 H-pyrazole-3-carboxylate
HC^O") NH2
N
N~ O
O NH2
H3C O

Palladium(II) hydroxide (100mg) was added to a solution of the nitro compound
of
preparation 29 (970mg, 3.39mmol) in methanol (20mL) and the mixture warmed to
reflux. Ammonium formate (1.07g, 16.97mmol) was added and the reaction mixture
stirred at reflux for 2 hours. The catalyst was removed by filtration through
Arbocel
and the reaction mixture concentrated in vacuo to yield the title product.

'H NMR (DMSO-D6, 400MHz) 8: 1.02 (t, 3H), 3.33 (m, 2H), 3.66 (m, 2H), 4.80 (s,
3H), 4.57 (m, 2H), 5.11 (m, 2H), 7.49 (m, 2H), MS APCI+ m/z 257 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 38 using the appropriate
nitro-
pyrazoles of preparations 30, 31, 32, 33, 34, 35 and 36.

R6 NH2
,N
N~ O
/0 NH2
H3C O
No R6 Data

'H NMR (DMSO-Ds, 400MHz) 8: 0.98 (d, 6H),
3.48 (m, 1 H), 3.64 (m, 2H), 3.76 (s, 3H), 4.45
39 -(CH2)~OCH(CH3)2 (t, 2H), 5.14 (m, 2H), 7.50 (m, 2H). MS ES+
m/z 293 [MNa]+

'H NMR (CDCI3, 400MHz) S: 1.10 (d, 3H),
40 -(CH2)2CH(CH3)OCH3 1.90 (m, 2H), 3.25 (s, 3H), 3.30 (m, 1 H), 3.90
(s, 3H), 4.50 (m, 2H), 4.92 (m, 2H), 6.50 (m,


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2H). MS APCI+ m/z 271 [MH]+

'H NMR (CDCI3, 400MHz) S: 3.30 (s, 3H),
3.50 (m, 2H), 3.58 (m, 2H), 3.90 (s, 3H), 3.99
41 -(CH~)2O(CH~)~OCH3 (t, 2H), 4.50 (t, 2H). MS APCI+ m/z 309
[MNa]+

CH3 'H NMR (DMSO-D6, 400MHz) 6: 1.04 (d, 3H),
, 0 " CH 3.12 (s, 3H), 3.65 (m, 1 H), 3.78 (s, 3H), 4.30
H3C3
42
2 (m, 1 H), 4.44 (m, 1 H), 5.10 (m, 2H), 7.48 (m,
2H). MS APCI+ mlz 257 [MH]+

'H NMR (CDCI3, 400MHz) 8: 0.12 (m, 2H),

43 ~OCH2 0.50 (m, 2H), 0.97 (m, 1 H), 3.30 (d, 2H), 3.92
(m, 5H), 4.53 (t, 2H). MS ES+ m/z 305
[MNa]+

O 'H NMR (DMSO-D6, 400MHz) 8: 1.19 (m, 2H),
1.30 (m, 2H), 1.96 (m, 1 H), 3.20 (m, 2H); 3.76
44 CH2 (m, 5H), 4.28 (d, 2H), 5.10 (m, 2H), 7.44 (m,

2H). MS APCI+ m/z 283 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.27 (m, 1 H),
aCH2 1.52 (m, 3H), 1.67 (m, 1 H), 1.87 (m, 1 H), 3.38
45 (m, 1 H), 3.78 (m, 1 H), 3.88 (s, 3H), 3.94 (m,
1 H), 4.30 (m, I H), 4.45 (m, 1 H). MS APCI+
m/z 283 [MH]+

Preparation 46
Methyl 4-amino-5-carbamoyl-l-(2-methoxyethyl)-1 H-pyrazole-3-carboxylate
H3C,o") NH2
N
N~

/0 NH2
H3C 0


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The nitro compound of preparation 28 (1.OOg, 3.7mmol) was dissolved in ethyl
acetate (15mL) and treated with 10% Pd/C (100mg). The reaction mixture was
stirred at room temperature under 15psi of hydrogen for 18 hours. The reaction
mixture was filtered through Arbocel , washing with ethyl acetate and the
filtrate
concentrated in vacuo. The residue was purified by column chromatography on
silica
gel eluting with pentane:ethyl acetate 50:50 to 34:66 to 0:100 to yield the
title
product.

'H NMR (DMSO-D6, 400MHz) 6: 3.16 (s, 3H), 3.60 (m, 2H), 3.76 (s, 3H), 4.45 (m,
2H), 5.07 (m, 2H), 7.42 (m, 2H). MS ES+ m/z 244 [MH]+

Preparation 47
Methyl 5,7-dioxo-l-(2-propoxyethyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-
dJpyrimidine-
3-carboxylate
H3C,,,,-\o -*o-) O
"IN
NH
O
H3C 0 H O

The amide of preparation 37 (9g, 33mmol) and N,N'-carbonyldiimidazole (5.4g,
33mmol) were dissolved in N,N-dimethylformamide (400mL) and the reaction
mixture stirred at room temperature for 30 minutes and then at 75 C for 18
hours.
Addditional N,N'-carbonyldiimidazole (400mg, 2.69mmol) was added and the
reaction mixture stirred for a further 90 minutes. The reaction mixture was
concentrated in vacuo and the residue taken up in water and stirred for 30
minutes.
The precipitate formed was filtered off to yield the title product as a pale
pink solid,
6.05g.

'H NMR (DMSO-D6, 400MHz) 8: 0.72 (t, 3H), 1.37 (q, 2H), 3.28 (t, 2H), 3.76 (t,
2H),
3.82 (s, 3H), 4.64 (t, 2H), 10.77 (s, 1 H), 11.37 (s, 1 H). MS APCI- m/z 295,
[M-H]"


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Preparation 48
Methyl 1-(2-ethoxyeth rl -5,7-dioxo-4 5 6 7-tetrahydro-lH-pyrazolo[4,3-
dlpyrimidine-
3-carboxklate
H3CO~-) O
,N
N\ ~ NH
O H~
H3C 0 0

A solution of the amide of preparation 38 (570mg, 3.38mmol) in N,N-
dimethylformamide (30mL) was treated with N,N'-carbonyldiimidazole (658mg,
4.06mmol) and the reaction mixture stirred at room temperature for 1 hour and
then
at 90 C for 18 hours. The reaction mixture was concentrated in vacuo and the
crude
product suspended in acetone and sonicated for 30 minutes. The solid product
was

filtered off and dried in vacuo to yield the title product.
'H NMR (DMSO-D6, 400MHz) S: 1.02 (t, 3H), 3.37 (m, 2H), 3.77 (m, 2H), 4.83 (s,
3H), 4.63 (m, 2H), 10.75 (s, I H), 11.40 (s, I H). MS ES- m/z 281 [M-H]-

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 48, using the appropriate
amide of
preparations 39, 40, 41, 42, 43 and 46.

R6
1 O
,N
N\ / NH
0 N-\
H3C ~'H O
No. R6 Data
'H NMR (DMSO-D6, 400MHz) 8: 0.95 (d, 6H),
3.47 (m, 1 H), 3.73 (t, 2H), 3.80 (s, 3H), 4.58 (t,
49 -(CHZ)ZOCH(CH3)2 2H), 10.78 (m, 1 H), 11.47 (m, 1 H). MS ES+

m/z 319 [MNa]+


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'H NMR (DMSO-D6, 400MHz) S: 1.02 (d, 3H),

50 -(CH2)2CH(CH3)OCH3 (m, 2H), 3.17 (s, 3H), 3.30 (m, 1 H), 3.80
3
(s, 3H), 4.50 (t, 2H), 7.00 (m, 1 H), 7.60 (m,
1 H). MS APCI- m/z 295 [M-H]"

'H NMR (DMSO-D6, 400MHz) 8: 3.15 (s, 3H),
51 -(CH2)O(CH2)20CH3 3.30 (t, 2H), 3.45 (t, 2H), 3.80 (t, 5H), 4.60 (t,
2H). MS APCI+ m/z 311 [M-H]"

CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.07 (d, 3H),
, 0 "CH 3.14 (s, 3H), 3.74 (m, 1 H), 3.82 (s, 3H), 4.40
52 H3C3
2 (m, 1 H), 4.60 (m, 1 H), 10.76 (m, 1 H), 11.37 (m,
1 H). MS APCI+ m/z 283 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 0.06 (m, 2H),
OCH2 0.35 (m, 2H), 0.83 (m, 1 H), 3.16 (d, 2H), 3.78
53 ~
(t, 2H), 3.81 (s, 3H), 4.61 (t, 2H), 10.77 (m,
I H), 11.37 (m, I H). MS ES+ m/z 331 [MNa]+
'H NMR (DMSO-D6, 400MHz) S: 3.17 (s, 3H),
54 -(CH2)20CH3 (m, 2H), 3.80 (s, 3H), 4.61 (m, 2H), 10.74
3
(m, 1 H), 11.37 (m, 1 H). MS ES+ m/z 269
[MH]+

Preparation 55
Methyl ropyra r4=ylmethyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-
dlpyrimidine-3-carboxylate
O
O
,N
N~ ~ NH
~ N-~
H3C O H 0


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The amide of preparation 44 (9.8g, 34.9mmol) was dissolved in acetonitrile
(100mL)
and the solution treated with N,N'-carbonyldiimidazole (6.8g, 42mmol). The
reaction
mixture was heated to reflux for 18 hours before being allowed to return to
room
temperature. The white precipitate formed was removed by filtration, washed
with
acetonitrile and dried in vacuo to yield the title product.

'H NMR (DMSO-D6, 400MHz) 8: 1.24 (m, 2H), 1.36 (m, 2H), 2.08 (m, 1 H), 3.21
(m,
2H), 3.80 (m, 2H), 3.83 (s, 3H), 4.40 (d, 2H), 10.78 (m, 1 H), 11.37 (m, 1 H)
MS APCI- m/z 307 [M-H]-

Preparation 56
Methyl 5,7-dioxo-1-(tetrahydropyran-2-ylmethyI)-4,5,6,7-tetrahydro-1 H-p
r~lo[4,3-
dlpyrimidine-3-carboxylate
C O
O
~N
N~ ~ NH
sO N--\
H3C O H O

The title compound was prepared by a method similar to that described for
preparation 55 using the amide of preparation 45.

'H NMR (DMSO-D6, 400MHz) 8: 1.20 (m, 1 H), 1.40 (m, 3H), 1.52 (d, 1 H), 1.75
{m,
1 H), 3.22 (m, 1 H), 3.74 (m, 2H), 3.80 (s, 3H), 4.40 (m, 1 H), 4.58 (m, 1 H),
10.75 (m,
1 H), 11.35 (m, 1 H). MS APCI+ m/z 309 [MH]+

Preparation 57
Methyl 5,7-dichloro-1-(2-propoxyethyl)-1 H-pyrazolo[4,3-djpyrimidine-3-
carboxylate
H3C,/"O
CI
N
O N
H3C 0 CI


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The dione of preparation 47 (3g, 10mmol), phosphorous oxychloride (14.2mL,
152mmol) and tetraethylammonium chloride (3.95g, 30mmol) were dissolved in
propionitrile (80mL) and the reaction mixture heated at 115 C for 18 hours.
The
reaction mixture was concentrated in vacuo and the residue dissolved in
additional
propionitrile (80mL) and treated with additional phosphorous oxychloride
(15mL,
145mmol). The reaction mixture was then heated to 115 C for a further 18
hours.
The reaction mixture was concentrated in vacuo and the residue azeotroped with
toluene. The crude product was taken up in ethyl acetate and cautiously
treated with
water. The two layers were separated and the aqueous layer re-extracted with
ethyl
acetate (x3). The combined organics were washed with brine, dried over
magnesium
sulphate and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel eluting with pentane:ethyl acetate 75:25 to yield
the
title product, 3.1g.
'H NMR (DMSO-D6, 400MHz) 8: 0.65 (t, 3H), 1.33 (q, 2H), 3.26 (t, 2H), 3.82 (t,
2H),
3.93 (s, 3H), 4.94 (t, 2H). MS APCI+ m/z 333, [MH]+

Preparation 58
Methyl 5,7-dichloro-l-(2-ethoxyethyl)-1 H-pyrazolof4,3-dlpyrimidine-3-carbox
Iate

H3Ccl
N
N
O N~
'
H3C CI

Phosphorous oxychloride (934 L, 10.Ommol) and tetraethylammonium chloride
(1 95mg, 1.50mmol) were added to a solution of the dione of preparation 48
(140mg,
0.50mmol) in propionitrile (5mL) and the reaction mixture refluxed for 18
hours. The
reaction mixture was concentrated in vacuo and the crude product partitioned
between ethyl acetate (50mL) and water (50mL). The organic layer was dried
over
magnesium sulphate and concentrated in vacuo. The crude product was purified
by
column chromatography on silica gel eluting with pentane:ethyl acetate 100:0
to
75:25 to yield the title product.


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'H NMR (CDCI3, 400MHz) 8: 1.05 (t, 3H), 3.41 (m, 2H), 3.84 (m, 2H), 4.06 (s,
3H),
5.00 (m, 2H). MS APCI+ m/z 319 [MH]+

Preparation 59
Methyl 5,7-dichloro-l-(2-isopropoxyethyl)-1 H-pyrazolor4,3-dlpyrimidine-3-
carboxylate
CH

H CO
3 "'~) CI
N"IN
\ ~ ~N

O N~
'
H3C 0 CI

The dione of preparation 49 (2.37g, 8.OOmmol) was suspended in acetonitrile
(30mL) and the solution treated with phosphorous oxychloride (15mL,.160mmol)
and
tetraethyl ammonium chloride (3.97g, 24mmol). The reaction mixture was stirred
at
reflux for 18 hours. The reaction mixture was allowed to cool and then
concentrated
in vacuo before being partitioned between dichloromethane (300mL) and water
(200mL). The dichloromethane layer was separated, dried over magnesium
sulphate
and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel eluting with pentane:ethyl acetate 100:0 to 75:25
to
yield the title product as a white solid, 1.54g.
'H NMR (CDCI3, 400MHz) 8 0.96 (d, 6H), 3.43 (m, 1 H), 3.86 (t, 2H), 4.08 (s,
3H),
4.96 (t, 2H). MS ES+ m/z 355 [MNa]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 59 using the appropriate
dione of
preparations 50, 51, 52, 54, 55 and 56.


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R6
1 CI
N
N ~ N
O N~
'
H3C O CI
No. R6 Data
'H NMR (CDCI3, 400MHz) 8: 1.18 (d, 3H), 2.00-
60 -(CH2)2CH(CH3)OCH3 2.15 (m, 2H), 3.20 (s, 3H), 3.30 (m, 1 H), 4.01
(s, 3H), 4.90 (t, 2H). MS APCI+ m/z 333 [MH]+
'H NMR (CDCI3, 400MHz) S: 3.20 (s, 3H), 3.30

61 -(CH2)20(CH2)20CH3 (t, 2H), 3.45 (t, 2H), 3.99 (t, 2H), 4.10 (s, 3H),
5.00 (t, 2H)

CH3 'H NMR (CDCI3, 400MHz) S: 1.24 (d, 3H), 3.12
62 H3C0 , 0''"CH2 (s, 3H), 3.84 (m, 1 H), 4.08 (s, 3H), 4.65 (m,
1 H), 4.94 (m, 1 H). MS APCI+ m/z 319 [MH]+
'H NMR (CDCI3, 400MHz) 5: 3.25 (s, 3H), 3.84
63 -(CH2)20CH3 (m, 2H), 4.09 (s, 3H), 4.98 (m, 2H). MS APCI+
m/z 305 [MH]+

O 'H NMR (CDCI3, 400MHz) 8: 1.45 (m, 2H), 1.54
(m, 2H), 2.30 (m, 1 H), 3.32 (m, 2H), 3.98 (m,
64 CHZ 2H), 4.07 (s, 3H), 4.73 (s, 2H). MS APCI+ m/z

345 [MH]+

'H NMR (CDC13, 400MHz) 5: 1.34-1.60 (m, 4H),
65 aCH 1. 66 (m, 1 H), 1.89 (m, 1 H), 3.23 (m, 1 H), 3.81
2 (m, 2H), 4.07 (s, 3H), 4.67 (m, 1 H), 4.96 (m,
I H). MS APCI+ m/z 345 [MH]+


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Preparation 66
Methyl 5,7-dichloro-l-(2-(cyclopropylmethoxy)ethyl)-1 H-pyrazolo[4,3-
dlpyrimidine-3-
carboxylate
CI
N~N
N
'O CI
HsC
O
The dione of preparation 53 (2.52g, 8.17mmol) was suspended in acetonitrile
(40mL) and the suspension treated with phosphorous oxychloride (15mL,
163.4mmol) and tetraethylammonium chloride (4.08g, 24.51 mmol). The reaction
mixture was heated at reflux for 24 hours. The reaction mixture was
concentrated in
vacuo and the residue triturated with ether. The filtrate was concentrated in
vacuo
and purified by column chromatography on silica gel eluting with
dichloromethane:ethyl acetate 50:50 to yield the title product as a colourless
oil,
907mg.
'H NMR (CDCI3, 400MHz) b: 0.03 (m, 2H), 0.40 (m, 2H), 0.82 (m, 1 H), 3.18 (d,
2H),
3.92 (t, 2H), 4.07 (s, 3H), 4.99 (t, 2H). MS ES+ m/z 345 [MH]+

Preparation 67
Methyl 5-chloro-7-(4-methylpyridin-2-ylamino)-1-(2-propoxyethyl)-1 H-
pyrazolo[4,3-
dl pyrimidine-3-carboxylate

N-
H3CO N \ /
'N CH
N\ N s
O N~
'
H3C p CI

The dichloro compound of preparation 57 (400mg, 1.2mmol) and 2-amino-4-
methylpyridine (649mg, 6.Ommol) were dissolved in dimethyl sulphoxide (5mL)
and
the reaction mixture stirred at 30 C for 1 hour. The reaction mixture was
partitioned


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between dichloromethane and water and the aqueous layer extracted with
dichloromethane (x2). The combined organics were washed with water (x2),
aqueous citric acid and brine before being dried over magnesium sulphate and
concentrated in vacuo to yield the title product as a yellow solid, 800mg.

MS APCI+ m/z 405 [MH]+
Preparations 68 to 71
IR6 N,R1
NZN
\ ~ ~N
O N~
H3C O CI

The following compounds of the general formula above were prepared by a method
similar to that described for preparation 67 using the appropriate dichloro
starting
material of preparations 58 and 63, and the appropriate HNR'R2 amine.

No.

CH3
68 R' ; R6 = -(CH2)2OCH2CH3

'H NMR (DMSO-D6, 400MHz) S: 1.01 (t, 3H), 2.26 (s, 3H), 3.52 (m,
2H), 3.88 (m, 5H), 4.96 (m, 2H), 7.76 (m, 1 H), 8.03 (m, 1 H), 8.20 (m,
1 H). MS APCI+ m/z 391 [MH]+

N
69 R' = I / ; R6 = -(CH2)2OCH3
CH3

'H NMR (CDCI3, 400MHz) S: 2.46 (s, 3H), 3.47 (m, 3H), 3.95 (m, 2H),
4.04 (s, 3H), 5.01 (m, 2H), 6.92 (m, 2H), 8.16 (m, 1 H). MS APCI+ m/z
377 [MH]+


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70 R' R 6 = -(CH2)2OCH2CH3

'H NMR (CD30D, 400MHz) 8: 1.16 (t, 3H), 1.85 (m, 2H), 2.16 (m, 2H),
2.48 (m, 2H), 3.58 (q, 2H), 3.90 (t, 2H), 3.98 (s, 3H), 4.64 (m, 1 H), 4.79
(t, 2H). MS APCI+ m/z 354 [MH]+

71 R' = OA ; R6 = -(CH2)2OCH2CH3

'H NMR (CD3OD, 400MHz) S: 0.73 (m, 2H), 0.92 (m, 2H), 1.19 (t, 3H),
2.99 (m, 1 H), 3.53 (q, 2H), 3.88 (t, 2H), 4.00 (s, 3H), 4.74 (t, 2H). MS
APCI+ m/z 340 [MH]+

Preparation 72
Methyl 5-chloro-l-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-
pyrazolo[4,3-
dlpyrimidine-3-carbox I~

H3C0 N
~
N\ N CH3
O
H3C O Ci

The dichloro compound of preparation 58 (1.98g, 6.20mmol) was dissolved in
dimethyl sulphoxide (10mL) and the solution treated with 2-amino-4-
methylpyridine
(1.34g, 12.4mmol). The reaction mixture was stirred at room temperature for 18
hours. The reaction mixture was partitioned between dichloromethane (300mL)
and
water (500mL) and the dichloromethane layer separated. The organic phase was
washed with water (3x100mL), dried over magnesium sulphate and concentrated in
vacuo. The residue was purified by column chromatography on silica gel eluting
with
dichloromethane:methanol 100:0 to 98:2. The crude product was triturated with
ether (50mL), filtered and concentrated in vacuo to yield the title product,
1.2g.


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'H-NMR (CDC13, 400MHz) 6: 1.06 (t, 3H), 2.49 (s, 3H), 3.62 (m, 2H), 4.00 (t,
2H),
4.06 (s, 3H), 5.05 (m, 2H), 6.98 (m, 1 H), 8.16 (m, 1 H), 8.50 (m, 1 H). MS
APCI+ m/z
391 [MH]+

Preparations 73 to 85
The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 72 using the appropriate HNR1
R2
amine and the appropriate dichloro compound of preparations 58 and 61.


H3CC N-R1
N
N

O N~
H3C 0 CI
No. R' Data

'H NMR (CD30D, 400MHz) 8: 1.14 (t, 3H), 1.72 (m,
73 2H), 2.08 (m, 2H), 3.57 (m, 4H), 3.91 (t, 2H), 3.97
(t, 2H), 4.02 (m, 2H), 4.40 (s, 3H), 4.79 (t, 2H)

'H NMR (CD39D, 400MHz) 8: 1.21 (t, 3H), 3.68 (q,
N~ F
74 2H), 4.03 (t, 2H), 4.08 (s, 3H), 4.89 (t, 2H), 7.55 (m,
I H), 8.20 (d, 1 H), 8.50 (m, I H). MS APCI+ m/z 395
[MH]+

0 CH3 'H NMR (CDCI3, 400MHz) 8: 1.24 (t, 3H), 3.71 (q,
2H), 3.92 (s, 3H), 4.02 (t, 2H), 4.07 (s, 3H), 4.90 (t,
75 N
/ 2H), 6.54 (d, 1 H), 7.67 (t, 1 H), 7.95 (d, 1 H). MS
APCI+ m/z 407 [MH]+


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'H NMR (CDCI3, 400MHz) 8: 1.21 (t, 3H), 3.67 (q,

76 I\ 2H), 4.06 (t, 2H), 4.07 (s, 3H), 4.86 (t, 2H), 7.17 (t,
/ 1 H), 7.41 (m, 2H), 7.71 (d, 2H). MS APCI+ m/z 376
[MH]+

'H NMR (CDC13, 400MHz) b: 1.21 (t, 3H), 3.68 (q,
2H), 4.06 (t, 2H), 4.08 (s, 3H), 4.87 (t, 2H), 6.86 (m,
77
F 1 H), 7.08 (m, 1 H), 7.38 (m, 1 H), 7.66 (m, 1 H). MS
APCI+ m/z 394 [MH]+

'H NMR (CDCI3, 400MHz) S: 1.11 (t, 3H), 3.62 (q,
F ~
78 2H), 4.00 (t, 2H), 4.08 (s, 3H), 4.88 (t, 2H), 7.14 (m,
2H), 7.23 (m, 1 H), 8.42 (t, 1 H), 9.49 (m, 1 H). MS
APCI+ m/z 394 [MH]+

CH3 'H NMR (CDCI3, 400MHz) 6: 1.09 (t, 3H), 2.39 (s,
\ 3H), 3.60 (q, 2H), 3.98 (t, 2H), 4.07 (s, 3H), 4.86 (t,
79 I/ / 2H), 6.94 (m, 1 H), 7.04 (t, 1 H), 8.21 (d, 1 H), 9.42
F (m, 1 H). MS APCI+ m/z 408 [MH]+

CH3 'H NMR (CDCI3, 400MHz) b: 1.20 (t, 3H), 2.27 (s,
80 CH3 3H), 2.31 (s, 3H), 3.66 (q, 2H), 4.04 (t, 2H), 4.07 (s,
I/ 3H), 4.84 (t, 2H), 7.16 (d, 1 H), 7.41 (s, 1 H), 7.47 (d,
I H), 9.31 (s, I H). MS APCI+ m/z 404 [MH]+

CH3 'H NMR (CDCI3, 400MHz) 8: 1.13 (t, 3H), 2.39 (s,
81 3H), 3.62 (q, 2H), 4.00 (s, 3H), 4.02 (t, 2H), 4.93 (t,
I/ 2H), 7.02 (d, 1 H), 7.28 (t, 1 H), 7.54 (s, 1 H), 7.61 (d,
1 H). MS APCI+ m/z 390 [MH]+

'H NMR (CDCI3, 400MHz) 8: 1.20 (t, 3H), 1.50 (m,
82 2H), 1.71 (m, 4H), 2.21 (m, 2H), 3.56 (q, 2H), 3.93
(m, 2H), 4.02 (s, 3H), 4:47 (m, I H), 4.67 (t, 2H),
7.35 (d, 1 H). MS ES+ m/z 368 [MH]+


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'H NMR (CDCI3, 400MHz) b: 1.13 (t, 3H), 2.04 (m,
83 H O 1 H), 2.45 (m, 1 H), 3.56 (q, 2H), 3.83 (m, 2H), 3.91
(t, 2H), 3.97 (s, 3H), 4.02 (m, 2H), 4.76 (m, 1 H),
4.79 (m, 2H). MS ES+ m/z 356 [MH]+

CH3 'H NMR (DMSO-D6, 400MHz) S: 1.03 (m, 3H), 2.35
84 N (s, 3H), 2.43 (m, 3H), 3.54 (m, 2H), 3.87 (m, 5H),
4.96 (m, 2H), 6.92 (m, 1 H), 7.65 (m, 1 H). MS
CH3 APCI+ m/z 405 [MH]+
H3CO\/\O N
85 ~N CH3
N~ ~ N
O N~
'
H3C O CI

'H NMR (CDCI3, 400MHz) b: 2.50 (m, 3H), 3.40 (m, 3H), 3.70 (m, 2H),
4.10 (m, 7H), 5.10 (m, 2H), 7.02 (m, 2H), 8.18 (m, 1 H). MS APCI- m/z
419 [M-H]-

= Preparation 73 used tetrahydropyran-4-ylamine (WO 98/08855, Pg. 17, e.g.
3) as the HNR'R2 amine

= Preparation 75 used 6-methoxy-pyridin-2-ylamine (US 01/0047013, pg. 3,
example 2) as the HNR'R2 amine

= Preparation 83 used (3R)-tetrahydrofuran-3-ylamine tosylate as the HNR'R2
amine with leq of N-ethyldiisopropylamine.


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Preparation 86
Methyl 5-chloro-l-(3-methox b~yl)-7-(4-methylpyridin-2-ylamino)-1 H-
pyrazolo(4,3-
dlpyrimid ine-3-carboxylate

H3CN
H3C ~N
N~ ~ N CH3
4
H3C o Ci

The dichloro compound of preparation 60 (700mg, 2.11 mmol) and 4-methylpyridin-
2-
ylamine (1.14g, 10.54mmol) were dissolved in dimethyl sulphoxide (10mL) and
the
reaction mixture heated to 30 C under nitrogen for 3 hours. The reaction
mixture
was concentrated in vacuo and the residue taken up in dichloromethane (100mL)
and water (150mL). The layers were separated and the aqueous layer washed with
dichloromethane (50mL). The organics were combined, washed with water (100mL)
and citric acid (50mL) solution, dried over magnesium sulphate and
concentrated in
vacuo. The crude product was purified by column chromatography on silica gel
eluting with dichloromethane:methanol 100:0 to 99:1 to yield the title product
as a
yellow solid, 330mg.
'H NMR (CD3OD, 400MHz) 8: 1.20 (m, 3H), 2.10 (m, 2H), 2.45 (s, 3H), 3.30 (s,
3H),
3.40 (m, 1 H), 3.98 (s, 3H), 5.00 (m, 2H), 6.90 (m,1 H), 7.30 (m, 1 H), 8.00
(m, 1 H)
MS ES+ m/z 405 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 86 using the appropriate
HNR'R2
amine and dichloro compound of preparations 58, 59, 62, 64 and 65.


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N~
6 /
IR N ~
N
N ~ ~ N CH3
H3C p CI

No. R6 Data

'H NMR (CDCI3, 400MHz) 8: 0.94 (d, 6H), 2.62 (s,
87 -(CH2)2OCH(CH3)3H), 3.70 (m, 1 H), 3.95 (t, 2H), 4.07 (s, 3H), 5.24
2
(m, 2H), 7.16 (d, 1 H), 8.17 (d, 1 H), 8.84 (m, 1 H).
MS ES+ m/z 427 [MNa]+

CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.12 (d, 3H),

, 0 " CH 2.39 (s, 3H), 3.20 (s, 3H), 3.85 (s, 3H), 3.85 (m,
88 H3C2
2 1 H), 4.82 (d, 2H), 7.05 (d, 1 H), 7.78 (s, 1 H), 8.25
(d, 1 H). MS ES+ m/z 391 [MH]+

iH NMR (DMSO-D6, 400MHz) 8: 1.36 (m, 4H),
2.14 (m, 1 H), 2.42 (s, 3H), 3.18 (m, 2H), 3.77 (m,
89 O CH2 2H), 3.84 (s, 3H), 4.79 (d, 2H), 7.03 (d, 1 H), 7.67

(s, 1 H), 8.20 (d, 1 H). MS APCI+ m/z 417 [MH]+
'H NMR (DMSO-D6, 400MHz) 6: 1.24 (m, 1 H),
CiCH 1.45 (m, 3H), 1.72 (m, 1 H), 1.79 (m, 1 H), 2.40 (s,
90 3H), 3.39 (m, 1 H), 3.85 (m, 1 H), 3.90 (s, 3H), 3.96
(m, 1 H), 4.83 (m, 2H), 7.08 (m, 1 H), 7.82 (s, 1 H),
8.25 (m, 1 H). MS APCI+ m/z 417 [MH]+
H3CO-"*~) N_Rl

\ N
CI
H3C p

No. R' Data


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N 'H NMR (DMSO-D6, 400MHz) 8: 1.10 (t, 3H), 1.30
91 11 (t, 3H), 2.81 (q, 2H), 3.50 (q, 2H), 3.90 (m, 5H),
4.98 (t, 2H), 7.05 (d, 1 H), 7.90 (m, 2H), 13.50 (m,
CH3 1 H). MS APCI- m/z 403 [M-H]"

CH3 'H NMR (DMSO-D6, 400MHz) S: 0.94 (t, 3H), 2.06
92 F (s, 3H), 3.42 (q, 2H), 3.80 (t, 2H), 3.88 (s, 3H), 4.97
(t, 2H), 6.73 (t, 1 H), 7.20 (t, 1 H), 7.46 (m, 1 H). MS
APCI- m/z 408 [M-H]-

CH3 'H NMR (CDCI3, 400MHz) 8: 1.26 (t, 3H), 2.48 (s,
93 N 3H), 3.67 (q, 2H), 4.05 (t, 2H), 4.07 (s, 3H), 4.89 (t,
2H), 6.93 (d, 1 H), 7.67 (t, 1 H), 8.20 (d, 1 H), 10.19
(s, 1 H). MS APCI+ m/z 391 [MH]+

CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.10 (t, 3H), 1.30
94 N (t, 3H), 2.81 (q, 2H), 3.50 (q, 2H), 3.90 (m, 5H),
\
I 4.98 (t, 2H), 7.05 (d, 1 H), 7.90 (m, 2H), 13.50 (m,
1 H). MS APCI1 m/z 403 [M-H]-

'H NMR (CDC13, 400MHz) 8: 1.16 (t, 3H), 2.24 (s,

N CH3 3H), 2.36 (s, 3H), 3.62 (q, 2H), 4.00 (t, 2H), 4.06 (s,
95 CH 3H), 4.91 (t, 2H), 8.04 (m, 1 H), 8.27 (m, 1 H), 10.05
3
(m, 1 H). MS APCI+ m/z 405 [MH]+

'H NMR (CDCI3, 400MHz) S: 1.22 (t, 3H), 3.70 (q,
96 N~ 2H), 4.03 (t, 2H), 4.08 (s, 3H), 4.90 (t, 2H), 7.08 (t,
/ 1 H), 7.79 (t, 1 H), 8.35 (d, 1 H), 8.48 (d, 1 H), 10.22
(m, 1 H). MS APCI+ m/z 377 [MH]+

F F 'H NMR (CDCI3, 400MHz) S: 1.10 (t, 3H), 3.61 (q,
97 2H), 4.00 (t, 2H), 4.05 (s, 3H), 4.89 (m, 2H), 6.98
(m, 2H), 8.38 (s, 1 H), 9.40 (m, 1 H)

F 'H NMR (CDCI3, 400MHz) S: 1.20 (t, 3H), 3.67 (q,
98 F 2H), 4.05 (m, 5H), 4.83 (m, 2H), 7.30 (m, 2H), 7.80
(m, 1 H), 9.50 (s, 1 H)


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F 'H NMR (CDCI3, 400MHz) S: 1.11 (t, 3H), 3.70 (q,
99 2H), 4.10 (m, 5H), 4.85 (m, 2H), 6.61 (m, 1 H), 7.37
(m, 2H), 9.65 (s, 1 H)

F 'H NMR (CDCI3, 400MHz) 8: 1.10 (t, 3H), 3.62 (q,
100 F 2H), 4.01 (m, 2H), 4.10 (s, 3H), 4.90 (m, 2H), 6.99
1 H), 7.18 (m, 1 H), 8.18 (m, 1 H), 9.58 (s, 1 H).
MS APCI+ m/z 412 [MH]+

F a 'H NMR (CDCI3, 400MHz) b: 1.10 (t, 3H), 3.61 (q,
101 2H), 4.00 (t, 2H), 4.10 (s, 3H), 4.88 (m, 2H), 6.80
F (m, 1 H), 7.12 (m, 1 H), 8.38 (m, 1 H), 9.60 (s, 1 H)

= Preparation 95 was prepared using 2-amino-4,5-dimethylpyridine (J. Het.
Chem., 1981, 18 (8), 1613-1618, page 1616 as the HNR'R2 amine.

Preparation 102
Methyl 5-chloro-l-(2-(cyclopropylmethoxy)eth rLl)-7-(4-methylpyridin-2-
ylamino)-1 H-
pyrazolo[4,3-d]pyrimidine-3-carbox I ate

C-"') N
N/IN N CH3
O N~
H3C 0 CI

The dichloro compound of preparation 66 (900mg, 2.61 mmol) was dissolved in
dimethyl sulphoxide (10mL) and the solution treated with 4-methylpyridin-2-
ylamine
(1.13g, 10.46mmol). The reaction mixture was then stirred at 35 C in an oil
bath for
1 hour. The reaction mixture was allowed to cool and treated with water to
induce
precipitation of a solid. The crude product was filtered off and dried in
vacuo at 50 C
for 18 hours. The mother liquors were extracted with dichloromethane (2x5OmL)
and
then concentrated in vacuo. The combined solids were purified by column


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chromatography on silica gel eluting with dichloromethane:methanol 100:0 to
98:2.
The crude product was then re-purified by column chromatography on silica gel
eluting with dichloromethane:ethyl acetate 70:30 to yield the title product,
160mg.
'H NMR (CDCI3, 400MHz) 8: 0.05 (d, 2H), 0.27 (m, 2H), 0.92 (m, 1 H), 2.48 (s,
3H),
3.38 (d, 2H), 4.02 (m, 2H), 4.03 (s, 3H), 5.08 (m, 2H), 6.80 (m, I H), 7.00
(m, 1 H),
7.80 (m, 1 H), 8.18 (m, 1 H). MS ES+ m/z 439 [MNa]+

Preparation 103
Methyl 5-chloro-7-(c clohexyl)amino-1-(2-ethoxyethyl)-1 H-pyrazolo[4,3-
d[p,yrimidine-
3-carboxylate
H3C0 N
~N
N~ ~ N
O N~
H3C 0 CI

The dichloro compound of preparation 58 (2.50g, 7.84mmol) was dissolved in
tetrahydrofuran (10mL) and the solution treated dropwise with a solution of
cyclohexylamine (4.48mL, 39.20mmol) whilst being cooled on an ice bath. The
reaction mixture was stirred for 15 minutes at room temperature. The reaction
mixture was diluted with water (50mL) and ethyl acetate (50mL) and the
reaction
mixture stirred for 1 hour. The solid present was collected by filtration,
washed with
water and dried in vacuo. The ethyl acetate layer was separated and washed
with
water, dried over magnesium sulphate and concentrated in vacuo. The residue
was
triturated with ether to yield further solid. A total of 2.25g of the desired
product was
collected.

'H NMR (CDCI3, 400MHz) 8: 1.18 (t, 3H), 1.27 (m, 2H), 1.47 (m, 2H), 1.53-1.75
{m,
2H), 1.78 (rn, 2H), 2.12 (m, 2H), 3.76 (q, 2H), 3.92 (t, 2H), 4.00 (s, 3H),
4.12 (m, 1 H),
4.70 (t, 2H), 7.20 (d, 1 H). MS ES+ m/z 382 [MH]+


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Preparations 104 to 117

The appropriate monochloro compound (leq), the appropriate HNR3R4 amine (3-
5eq), N-ethyldiisopropylamine (5eq) and tetraethylammonium fluoride hydrate (1
eq)
were dissolved in 1-methyl-2-pyrrolidinone (5.3mL.mmol") and the reaction
vessel
sealed and heated in a microwave oven for 45 minutes. The reaction mixture was
allowed cool to room temperature before being partitioned between ethyl
acetate
(50mL) and water (50mL). The organic layer was washed with water (25mL), dried
over magnesium sulphate and concentrated in vacuo. The residue was purified by
column chromatography on silica gel eluting with dichloromethane:ethyl acetate
50:50 to yield the desired product.

The monochloro compounds of preparations 73, 74, 75, 76, 77, 81, 86, 87, 88,
92,
97 and 102 were used.


N-
R 6 N ~ ~

N\ ~ N CH3
O N CH3
H C N--~
3 0 / CH3
H3C
No. R6 Data

'H NMR (CD3OD, 400MHz) 8: 0.03 (m, 2H), 0.24
(m, 2H), 0.96 (m, 1 H), 1.25 (d, 6H), 2.40 (s, 3H),
104 0 CH2 3.09 (s, 3H), 3.38 (d, 2H), 3.94 (s, 3H), 3.98 (m,
2H), 4.81 (m, 2H), 5.15 (m, 1 H), 6.93 (d, 1 H),
8.15 (d, 1 H), 8.31 (s, 1 H). MS ES+ m/z 454
[MH]+


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'H NMR (CD3OD, 400MHz) b: 1.24 (m, 6H), 1.32
CH3 (m, 3H), 2.38 (s, 3H), 3.07 (s, 3H), 3.41 (s, 3H),
105 H3C,,0 ~CH2 3.92 (m, 1 H), 3.94 (s, 3H), 4.58 (m, 1 H), 4.68
(m, 1 H), 5.14 (m, 1 H), 6.93 (d, 1 H), 8.17 (d, 1 H),
8.22 (s, 1 H). MS APCI+ m/z 428 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.07 (d, 6H), 1.25
(d, 6H), 2.37 (s, 3H), 3.10 (s, 3H), 3.66 (m, 1 H),
106 -(CH2)2OCH(CH3)2 3.94 (s, 3H), 3.94 (m, 2H), 4.76 (t, 2H), 5.16 (m,
1 H), 6.93 (d, 1 H), 8.17 (d, 1 H), 8.32 (s, 1 H).
MS ES+ m/z 442 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 1.05 (m, 3H),
1.18-1.25 (m, 8H), 2.35 (s, 3H), 2.98 (s, 3H),
3.15 (s, 3H), 3.30 (m, 1 H) 3.80 (s, 3H), 4.65 (m,
107 -(CH2)2CH(CH3)OCH3
2H), 5.02 (m, I H), 6.95 (m, 1 H), 8.00 (m, 1 H),
8.20 (m, 1 H), 9.20 (m, I H). MS ES+ m/z 442
[MH]+

HsCO H ~
N-R
N

O N _R3
H3C O N
H3C
No. R' R3 Data

'H NMR (CD3OD, 400MHz) 8: 1.20 (t, 3H),
1.23 (d, 6H), 3.07 (s, 3H), 3.66 (q, 2H),
N ~
108 -CH(CH3)2 3.96 (s, 3H), 4.00 (t, 2H), 4.80 (t, 2H), 5.10
(m, 1 H), 7.64 (t, 1 H), 8.21 (s, 1 H), 8.32 (d,
1 H). MS APCI- m/z 430 [M-H]"


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'H NMR (CD3OD, 400MHz) 8: 1.14 (t, 3H),
CH3 1.22 (d, 6H), 2.30 (s, 3H), 3.04 (s, 3H),

109 F -CH(CH3)2 3.63 (q, 2H), 3.96 (s, 3H), 3.98 (t, 2H), 4.79
(t, 2H), 5.08 (m, 1H),7.02(t, 1H),7.42(m,
I H), 7.68 (m, 1 H). MS ES+ m/z 445 [MH]+
'H NMR (CD3OD, 400MHz) 8: 1.15 (t, 3H),
CH3 1.20 (t, 3H), 2.30 (s, 3H), 3.19 (s, 3H), 3.60
110 \ F -CH2CH3 (q, 2H), 3.70 (q, 2H), 3.96 (s, 3H), 3.98 (m,
2H), 4.80 (t, 2H), 7.01 (t, 1 H), 7.42 (t, 1 H),
7.67 (m, 1 H). MS APCI+ m/z 431 [MH]+
'H NMR (CD3OD, 400MHz) 6: 1.15 (t, 3H),
H3C10 1.23 (d, 6H), 3.05 (s, 3H), 3.65 (q, 2H),
111 N -CH(CH3)2 3.95 (s, 3H), 3.98 (q, 2H), 4.02 (s, 3H),
4.78 (t, 2H), 5.01 (m, 1 H), 6.49 (d, 1 H),
7.66 (t, 1 H), 7.82 (d, 1 H). MS APCI+ m/z
444 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.15 (t, 3H),
1.23 (d, 6H), 3.05 (s, 3H), 3.65 (q, 2H),
112 -CH(CH3)2 3.96 (s, 3H), 4.00 (t, 2H), 4.79 (t, 2H), 5.11
(m, 1 H), 7.09 (t, 1 H), 7.40 (t, 2H), 7.71 (d,
2H). MS APCI+ m/z 413 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.16 (t, 3H),
CH3 1.22 (d, 6H), 2.37 (s, 3H), 3.06 (s, 3H),
113 -CH(CH3)2 3.45 (q, 2H), 3.98 (t, 3H), 4.00 (t, 2H), 4.79
(t, 2H), 5.10 (m, 1 H), 6.93 (d, 1 H), 7.23 (t,
I H), 7.43 (d, 1 H), 7.65 (s, I H). MS APCI+
m/z 427 [M H]+

'H NMR (CD3OD, 400MHz) 8: 1.15 (t, 3H),
1.25 (d, 6H), 3.07 (s, 3H), 3.64 (q, 2H),
114 -CH(CH3)2 3.96 (s, 3H), 4.00 (t, 3H), 4.80 (t, 2H), 5.10
F
(m, 1 H), 6.80 (m, 1 H), 7.33 (m, 1 H), 7.44


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(m, 1 H), 7.78 (m, 1 H). MS APCI+ m/z 431
[MH]+
'H NMR (CDCI3, 400MHz) 8: 1.10 (t, 3H),
F ~ F 1.18 (d, 6H), 3.05 (s, 3H), 3.60 (q, 2H),
115 -CH(CH3)2 3.97 (t, 2H), 4.02 (s, 3H), 4.78 (m, 2H),
5.00 (m, 1 H), 6.90 (m, 2H), 8.18 (m, 1 H),
8.90 (s, 1 H). . MS APCI+ m/z 449 [MH]+
'H NMR (CD3OD, 400MHz) b: 1.15 (t, 3H),
1.20 (d, 6H), 1.69 (m, 2H), 2.15 (m, 2H),

116 CH CH (s, 3H), 3.56 (m, 4H), 3.88 (m, 2H),
O -
( 3)a 3.02 3.95 (s, 3H), 4.02 (m, 2H), 4.25 (m, 1 H),

4.66 (t, 2H), 5.12 (m, 1 H). MS ES+ m/z
421 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.15 (t, 3H),
1.70 (m, 2H), 2.13 (m, 2H), 3.19 (s, 6H),
117 -CH3 3.54 (m, 4H), 3.88 (t, 2H), 3.94 (s, 3H),
4.00 (m, 2H), 4.30 (m, 1 H), 4.65 (t, 2H).
MS ES+ mlz 393 [MH]+

Preparation 118
Methyl 5-(N-isopropyl-N-methylamino)-1-[2-(2-methoxyethoxy)ethyl]-7-(4-meth il-

pyridin-2-ylamino)-1 H-pyrazolo[4,3-cfl pyrimidine-3-carboxylate
H3CO N

N " CH3
/ N
N CH3
H C N--~
3 0 / CH3
H3C
The monochloro compound of preparation 85 (150mg, 0.36mmol), N-
ethyldiisopropylamine (186 L, 1.07mmol) and N-methyl-isopropylamine (50 L,


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_0.43mmol) were dissolved in dimethyl sulphoxide (1.5mL) and the reaction
mixture
stirred at 120 C for 18 hours. Additional N-methyl-isopropylamine (62 L,
0.36mmol)
was added and the reaction stirred at 120 C for a further 4 hours. The
reaction
mixture was concentrated in vacuo and the residue taken up in a mixture of
dichloromethane (50mL) and water (100mL). The two layers were separated and
the
aqueous layer washed with dichloromethane (50mL). The organics were combined
and washed with water (2x5OmL) before being dried over magnesium sulphate and
concentrated in vacuo. The crude product was purified by column chromatography
on silica gel eluting with dichloromethane:methanol 95:5 to yield the title
product as
a yellow oil, 65mg.
'H NMR (CD3OD, 400MHz) 8: 1.25 (d, 6H), 2.39 (s, 3H), 2.93 (m, 3H), 3.05 (s,
3H),
3.45 (t, 2H), 3.62 (m, 2H), 3.95 (s, 3H), 4.00 (t, 2H), 4.78 (m, 2H), 5.10 (m,
1 H), 6.90
(m, I H), 8.15 (d, 1 H),, 8.25 (m, 1 H). MS APCI+ m/z 458 [MH]+

Preparation 119
Methyl 5-(dimethylamino)-1-(2-ethoxyethyl)-7-(6-ethylpyridin-2-ylamino)-1 H-
p ray zolo[4,3-dlpyrimidine-3-carboxylate

~
H3C~0 N \

N N CH3
N

O N _CH
H3C O N s
H3C

A solution of the monochloro compound of preparation 94 (200mg, 0.50mmol) and
N-ethyldiisopropylamine (172 L, 0.99mmol) in dimethyl sulphoxide (2mL) was
treated with a 5.6M solution of dimethylamine in ethanol (180 L, 1.0mmol) and
the
reaction mixture stirred at 120 C for 18 hours. The reaction mixture was
concentrated in vacuo and the residue taken up in ether (100mL) and washed
with
water (50mL). The aqueous was extracted with ether (25mL) and the combined
organics washed with water (2x100mL) and brine (50mL), dried over magnesium
sulphate and concentrated in vacuo. The residue was purified by column


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chromatography on silica gel eluting with dichloromethane:methanol 100:0 to
95:5.
The crude product was recrystallised from ethanol to yield the title product.

'H NMR (CDCI3, 400MHz) 8: 1.30 (m, 6H), 2.76 (q, 2H), 3.30 (s, 6H), 3.70 (q,
2H),
4.01 (m, 2H), 4.02 (s, 3H), 4.80 (t, 2H), 6.83 (d, 1 H), 7.60 (t, 1 H), 8.10
(d, 1 H), 9.80
(s, I H). MS APCI- m/z 412 [M-H]-

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 119 using the appropriate
HNR3R4
amine and monochloro compound of preparations 72, 78, 79, 80, 92, 94, 96, 97,
98,
99, 100 and 101.

R 7A

N- R7a
H3C O N /
N~N R7c
/ X N
O N~ _R3
H3C O N
No. H3C
120 R3 -CH2CH3; R'A = H; R'B = H; R'C
=-CH3
'H NMR (CD3OD, 400MHz) b: 1.10 (t, 3H), 1.22 (t, 3H), 2.40 (s, 3H),
3.21 (s, 3H), 3.61 (q, 2H), 3.79 (q, 2H), 3.96 (m, 5H), 4.79 (t, 2H), 6.98
(d, 1 H), 8.17 (d, 1 H), 8.37 (s, 1 H). MS APCI+ m/z 414 [MH]+

121 R3 =-CH(CH3)2; R'A = H; R'B = H; R70 =-CH3

'H NMR (CDCI3, 400MHz) S: 1.16 (t, 3H), 1.24 (s, 6H), 2.36 (s, 3H),
3.11 (s, 3H), 3.60 (q, 2H), 3.94 (t, 2H), 4.02 (s, 3H), 4.77 (m, 2H), 5.15
(m, 1 H), 6.82 (m, 1 H), 8.18 (q, 1 H), 8.24 (s, I H). MS APCI+ m/z 426
[MH]+

122 R3 = -CH2CH3; R'A =-CH2CH3; R'B = H; R'C = -CH3

'H NMR (CD3OD, 400MHz) S: 1.20 (m, 6H), 1.30 (t, 3H), 2.78 (q, 2H),


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3.21 (s, 3H), 3.65 (q, 2H), 3.78 (q, 2H), 3.97 (m, 5H), 4.81 (m, 2H),
6.98 (d, I H), 7.70 (t, 1 H), 8.20 (d, 1 H). MS APCI- m/z 426 [M-H]-

123 R3 =-CH(CH3)2; R'" = H; R'B = H; R7 = H

'H NMR (CDCI3, 400MHz) 8: 1.20 (t, 3H), 1.25 (d, 6H), 3.12 (s, 3H),
3.64 (q, 2H), 3.98 (t, 2H), 4.03 (s, 3H), 4.79 (t, 2H), 5.15 (m, 1 H), 6.98
(m, 1 H), 7.68 (t, 1 H), 8.33 (t, 2H), 9.81 (m, 1 H). MS APCI+ m/z 414
[MH]+

R7B
R7a

7C
H3CQ N R

N~N R7D
N
O N _Rs
H3C 0 R4

124 R3 =-CH(CH3)2; R4 = -CH3; R'A = H; R'B = F; R'C = F; R7D = H

'H NMR (CDCI3, 400MHz) 8: 1.20 (t, 3H), 1.22 (d, 6H), 3.10 (s, 3H),
3.62(m,2H),4.00(m,5H),4.78(m,2H),5.10(m, 1H),7.10(m,2H),
7.80 (m, 1 H), 9.10 (s, 1 H). MS APCI+ m/z 449 [MH]+

125 R3 = -CH(CH3)2; R4 = -CH3; R'A = H; R'B = F; R'C = H; R7D = F

'H NMR (CDCI3, 400MHz) 5: 1.20 (t, 3H), 1.22 (d, 6H), 3.10 (s, 3H),
3.61 (q, 2H), 4.00 (m, 5H), 4.78 (m, 2H), 5.10 (m, 1 H), 6.50 (t, 1 H),
7.30 (m, 2H), 9.30 (s, 1 H). MS APCI+ m/z 449 [MH]+
126 R3 =-CH(CH3)2; R4 = -CH3; R' = F; R'B = H; R 7C = H; R'D = F

'H NMR (CDCI3, 400MHz) S: 1.10 (t, 3H), 1.20 (d, 6H), 3.12 (s, 3H),
3.58 (q, 2H), 3.95 (t, 2H), 4.02 (s, 3H), 4.78 (m, 2H), 5.10 (m, 1 H),
6.70 (m, 1 H), 7.05 (m, 1 H), 8.30 (m, 1 H), 9.20 (m, 1 H). MS APCI-
m/z 447 [M-H]-
127 R3 = -CH(CH3)2; R4 =-CH3; R'A = F; R7e = F; R 7C = H; R'D = H

'H NMR (CDCI3, 400MHz) S: 1.10 (t, 3H), 1.18 (d, 6H), 3.07 (s, 3H),
3.61 (q, 2H), 3.92 (t, 2H), 4.01 (s, 3H), 4.78 (m, 2H), 5.05 (m, 1 H),


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6.82 (m, 1 H), 7.03 (m, I H), 8.00 (m, 1 H). MS APCI- m/z 447 [M-H]-
128 R3 =-CH2CH3; R4 =-CH2CH3; R'A = H; R'B =-CH3; R'C = F; R7D = H

'H NMR (CDCI3, 400MHz) S: 1.20 (m, 9H), 2.30 (s, 3H), 3.65 (q, 2H),
3.70 (m, 4H), 4.00 (m, 5H), 4.75 (t, 2H), 6.95 (t, 1 H), 7.35 (m, 1 H),
7.60 (m, 1 H). MS APCI- m/z 443 [M-H]"-

129 R3 =-CH3; R4 = -CH3; R'A = F; R'B = H; R'1 = H; R7D = -CH3

'H NMR (CDCI3, 400MHz) 8: 1.10 (t, 3H), 2.35 (s, 3H), 3.26 (s, 6H),
3.59 (q, 2H), 3.95 (t, 2H), 4.03 (s, 3H), 4.77 (t, 2H), 6.84 (m, 1 H), 7.01
(m, 1 H), 8.25 (d, 1 H), 9.00 (s, 1 H). MS APCI+ m/z 417 [MH]+
130 R3 =-CH2CH3; R4 =-CH3; R'A = F; R'B = H; R'1 = H; R7D =-CH3

'H NMR (CDCI3, 400MHz) 6: 1.10 (t, 3H), 1.22 (t, 3H), 2.35 (s, 3H),
3.25 (s, 3H), 3.59 (q, 2H), 3.63 (q, 2H), 3.95 (t, 2H), 4.03 (s, 3H), 4.76
(t, 2H), 6.82 (m, 1 H), 7.02 (m, 1 H), 8.23 (d, 1 H), 8.98 (s, 1 H). . MS
APCI+ m/z 431 [MH]+
131 R3 =-CH3; R4 =-CH3; R'A = H; R'B =-CH3; R'C =-CH3; R7D = H

'H NMR (CDCI3, 400MHz) 6: 1.19 (t, 3H), 2.27 (s, 3H), 2.29 (s, 3H),
3.26 (s, 6H), 3.62 (q, 2H), 4.00 (t, 2H), 4.03 (s, 3H), 4.74 (t, 2H), 7.10
~
(d, 1 H), 7.40 (d, 1 H), 7.52 (s, 1 H), 8.90 (s, 1 H). MS APCI+ m/z 413
[MH]+

132 R3 =-CH2CH3; R4 =-CH3; R'A = H; R7e =-CH3; R'C =-CH3; R7D = H
'H NMR (CDCI3, 400MHz) b: 1.17 (t, 3H), 1.23 (t, 3H), 2.27 (s, 3H),
2.29 (s, 3H), 3.24 (s, 3H), 3.62 (q, 2H), 3.74 (q, 2H), 4.00 (t, 2H), 4.02
(s, 3H), 4.74 (t, 2H), 7.11 (d, 1 H), 7.36 (d, 1 H), 7.57 (s, 1 H), 8.89 (s,
1 H). MS APCI+ m/z 427 [MH]+
133 R3 =-CH(CH3)2; R4 =-CH3; R'" = F; R'B = H; R 7C = H; R' = H

'H NMR (CDCI3, 400MHz) 8: 1.10 (t, 3H), 1.21 (d, 6H), 3.08 (s, 3H),
3.61 (q, 2H), 3.96 (t, 2H), 4.03 (s, 3H), 4.78 (t, 2H), 5.01 (m, 1 H), 7.05
(m, 1 H), 7.14 (m, 2H), 8.29 (t, 1 H), 9.01 (m, 1 H). MS APCI+ m/z 431
[MH]+


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Preparation 134
Methyl 1-(2-(c clopropylmethoxy)ethyl)-5-(N-ethyl-N-methyl-amino)-7-(4-meth yI-

pyridin-2-ylamino)-1 H-pyrazolo [4,3-d[pyrimidine-3-carboxylate

O N
N~ N 1-1 N CH3
4 N~

H3C 0 H C CH3
3

A solution of the chloro compound of preparation 102 (40mg, 0.096mmol) and N-
ethyidiisopropylamine (83 L, 0.48mmol) in dimethyl sulphoxide (2mL) was
treated
with N-methylethylamine (41 L, 0.48mmol) and the reaction mixture stirred at
120 C
for 18 hours. The reaction mixture was allowed to cool and partitioned between
water (25mL) and ethyl acetate (25mL). The organic layer was washed with water
(25mL), dried over magnesium sulphate and concentrated in vacuo. The residue
was purified by column chromatography on silica gel eluting with ethyl acetate
to
yield the title product.

'H NMR (CD3OD, 400MHz) 8: 0.02 (m, 2H), 0.23 (m, 2H), 0.95 (m, 1 H), 1.24 (t,
3H),
2.37 (s, 3H), 3.21 (s, 3H), 3.35 (d, 2H), 3.76 (m, 2H), 3.95 (s, 3H), 3.98 (t,
2H), 4.79
(m, 2H), 6.94 (m, 1 H), 8.13 (d, 1 H), 8.32 (s, 1 H). MS ES+ m/z 462 [MNa]+
Preparation 135
5-Chloro-7-(4-methypyridin-2-ylamino)-1-(2-propoxyeth rLl)-1 H-pyrazolo[4,3-
d]pyrimidine-3-carboxylic acid

H3CO N
\
N~ \ N CH3
HO N~
O CI

The ester of preparation 67 (500mg, 1.24mmol) was dissolved in dioxan (5mL)
and
the solution treated with a 1 M aqueous solution of sodium hydroxide (6.20mL,


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6.2mmol). The reaction mixture was then stirred for 18 hours at room
temperature.
The reaction mixture was treated with 1 M citric acid solution (10mL) and a
yellow
precipitate formed. The mixture was stirred for 15 minutes before being
filtered and
the solid product dried in vacuo to yield the title product, 360mg.

'H NMR (CDCI3, 400MHz) 8: 0.73 (t, 3H), 1.52 (m, 2H), 2.51 (s, 3H), 3.51 (t,
2H),
4.01 (t, 2H), 5.05 (m, 2H), 6.98 (m, 1 H), 7.24 (m, 1 H), 8.14 (m, I H). MS
APCI+ m/z
391 [MH]+

The following compounds were prepared by a method similar to that described
for
preparation 135 using the appropriate ester of preparations 68, 69, 70, 71,
72, 80,
82, 83, 84, 87, 88, 89, 90, 91, 92, 93 and 103

N
6

N N
N~ / 'N CH3
HO N
O CI
No. R6 Data

'H NMR (DMSO-D6, 400MHz) S: 1.00 (t, 3H), 2.34
137 -(CH2)2OCH2CH (s, 3H), 3.45 (m, 2H), 3.81 (m, 2H), 4.84 (m, 2H),
3
6.93 (m, 1 H), 7.89 (m, 1 H), 8.16 (m, 1 H). MS ES-
m/z 375 [M-H]-

O 'H NMR (DMSO-D6, 400MHz) 8: 1.32 (m, 4H), 2.12
138 (m, 1 H), 2.38 (s, 3H), 3.20 (m, 2H), 3.78 .(m, 2H),
~ H2 4.76 (d, 2H), 6.90 (d, 1 H), 7.60 (s, 1 H), 8.30 (s, 1 H).
MS APCI+ m/z 403 [MH]+


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'H NMR (DMSO-D6, 400MHz) S: 1.22 (m, 1 H), 1.42

CiCH (m, 3H), 1.70 (m, 1 H), 1.85 (m, 1 H), 2.36 (s, 3H),
139 3.20-3.40 (m, 1 H), 3.85 (m, 1 H), 3.94 (m, 1 H), 4.78
2
(m, 2H), 6.99 (d, 1 H), 7,87 (m, 1 H), 8.20 (m, 1 H).
MS APCI+ m/z 403 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 2.21 (s, 3H), 3.25
149 -(CH2)20CH3 (m, 3H), 3.82 (m, 2H), 4.96 (m, 2H), 6.97 (m, 1 H),
7.77 (m, 1 H), 8.17 (m, 1 H). MS ES- m/z 361 [M-H]"
'H NMR (DMSO-D6, 400MHz) 8: 0.93 (d, 6H), 2.38

150 -(CH2)2OCH(CH3)(s, 3H), 3.54 (m, 1 H), 3.84 (m, 2H), 4.89 (m, 2H),
a
7.04 (m, 1 H), 7.90 (m, 1 H), 8.23 (m, 1 H). MS ES-
m/z 389 [M-H]"

CH3 'H NMR (DMSO-D6, 400MHz) 6: 1.13 (d, 3H), 2.43
151 H3C`0" CH (s, 3H), 3.20 (s, 3H), 3.86 (m, 1 H), 4.80 (d, 2H),
2 7.10 (d, 1 H), 7.80 (s, 1 H), 8.27 (d, 1 H). MS ES+
m/z 377 [MH]+

H3Cll~ O-") N_Rl
~N
N / \ N

HO N
O CI
No. R' Data

'H NMR (DMSO-D6, 400MHz) 8: 1.03 (t, 3H), 2.24
N~
136 CH3 (s, 3H), 3.50 (m, 2H), 3.86 (m, 2H), 4.88 (m, 2H),
7.77 (m, 1 H), 8.03 (m, 1 H), 8.17 (m, 1 H). MS
ES- m/z 375 [M-H]"


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N 'H NMR (DMSO-D6, 400MHz) 8: 1.02 (t, 3H), 1.22.

140 (t, 3H), 2.66 (q, 2H), 3.43 (m, 2H), 3.85 (m, 2H),
4.92 (m, 2H), 7.01 (m, 1 H), 7.95 (m, 1 H), 8.20 (m,
CH3
1 H). MS ES- m/z 389 [M-H]"

'H NMR (DMSO-D6, 400MHz) S: 0.63 (m, 2H),
141 AA 0.82 (m, 2H), 0.97 (t, 3H), 2.94 (m, 1 H), 3.39 (m,
2H), 3.71 (m, 2H), 4.77 (m, 2H), 7.80 (m, 1 H) .
MS ES- m/z 324 [M-H]"

'H NMR (DMSO-D6, 400MHz) 8: 0.99 (t, 3H), 1.77
142 n (m, 2H), 2.14 (m, 2H), 2.35 (m, 2H), 3.40 (m, 2H),
~I
3.75 (m, 2H), 4.59 (m, 1 H), 4.81 (m 2H), 6.72 (m,
1 H) . MS ES- m/z 338 [M-H]-

'H NMR (DMSO-D6, 400MHz) S: 1.00 (t, 3H), 1.58
143 (m, 4H), 1.75 (m, 2H), 2.03 (m, 2H), 3.41 (m, 2H), w,,o 3.73 (m, 2H), 4.62
(m, 1 H), 4.79 (m, 2H), 7.44 (m,

I H) . MS ES- m/z 352 [M-H]-

'H NMR (CDCI3, 400MHz) 8: 1.00 (t, 3H), 1.18 (m,
1 H), 1.38 (m, 4H), 1.62 (m, 1 H), 1.74 (m, 2H),
144 1.96 (m, 2H), 3.40 (t, 2H), 3.72 (m, 2H), 4.03 (m,
1 H), 4.73 (m, 2H), 7.26 (d, 1 H). MS ES- m/z 366
[M-H]-

'H NMR (DMSO-D6, 400MHz) 8: 1.20 (t, 3H), 1.96
H O
145 (m, 1 H), 2.49 (m, 1 H), 3.61 (q, 2H), 3.86 (m, 2H),
3.94 (t, 2H), 4.04 (m, 2H), 4.75 (t, 2H), 4.85 (m,
1 H), 7.70 (m, 1 H)

CH3 'H NMR (CD3OD, 400MHz) 8: 1.11 (t, 3H), 2.40
146 N (s, 3H), 2.49 (s, 3H), 3.58 (m, 2H), 3.97 (m, 2H),
5.01 (m, 2H), 6.92 (m, 1 H), 7.94 (m, 1 H). . MS
CH3 ES- m/z 389 [M-H]"


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CH3 'H NMR (CD3OD, 400MHz) S: 1.08 (t, 3H), 2.26
~
147 ~ (s, 3H), 2.38 (s, 3H), 3.65 (q, 2H), 3.98 (t, 2H),
/ CH3 4.99 (t, 2H), 7.95 (m, 1 H), 8.00 (s, 1 H). MS
APCI+ m/z 391 [MH]+

CH3 'H NMR (CD3OD, 400MHz) S: 1.08 (t, 3H), 2.45
148 N (s, 3H), 3.52 (q, 2H), 3.85 (t, 2H), 4.92 (t, 2H),
7.01 (d, 1 H), 7.82 (t, 1 H), 7.94 (d, 1 H). MS
APCI+ m/z 377 [MH]+

F 'H NMR (CD3OD, 400MHz) 6: 0.95 (t, 3H), 2.27
152 (s, 3H), 3.45 (q, 2H), 3.82 (t, 2H), 4.04 (t, 2H),
CH3 7.22 (t, 1 H), 7.51 (m, 2H), 9.35 (s, 1 H). MS
APCI- m/z 392 [MNa]+
Preparation 153
f5,7-Dichloro-l-(2-ethoxyethyl)-1 H-pyrazolo[4,3-dlpyrimidin-3-yllmethanol

H3C1-1~ O""") CI
~N
N~ \ N

HO N
CI
The dichloro compound of preparation 58 (2.4g, 7.52mmol) was dissolved in
tetrahydrofuran (60mL) and the solution cooled to -78 C. Diisobutylaluminium
hydride (37.6mL, 37.6mmol) in tetrahydrofuran (20mL) was added dropwise over
10
minutes and the reaction mixture stirred at -78 C for 10 minutes and then at -
10 C

for 1 hour. The reaction mixture was cooled to -78 C, quenched with ammonium
chloride solution (25mL) and allowed to return to room temperature. The
reaction
mixture was diluted with dichloromethane (200mL) and water (100mL) and the
solution filtered through Arbocel , washing through with dichloromethane
(3x100mL). The organic phase was separated, dried over magnesium sulphate and
concentrated in vacuo. The crude product was purified by column chromatography


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on silica gel eluting with dichloromethane:methanol 99:1 to yield the title
product,
1.67g.

'HNMR (CDCI3, 400MHz) 8: 1.08 (t, 3H), 3.42 (m, 2H), 3.80 (m, 2H), 4.90 (m,
2H),
5.10 (s, 2H). MS APCI+ m/z 291 [MH]+

Preparation 154
3-(tert-Butyldimeth Isilyloxymethyl)-5,7-dichloro-1-(2-ethoxyethyl)-1 H-
pyrazoloj4,3-
d]pyrimidine
H3C11~ O"-") CI

N
H3C\ O N
Si CI
~ `CH3
H3C-/
H3C CH3

The alcohol of preparation 153 (1.32g, 4.53mmol) was dissolved in
dichloromethane
(25mL) and the solution treated with imidazole (339mg, 4.98mmol) and then tert-

butyldimethylsilyl chloride (750mg, 4.98mmol). The reaction mixture was then
stirred
at room temperature for 18 hours. The reaction mixture was diluted with
dichloromethane (200mL) and washed with 10% potassium carbonate solution
(100mL). The organic phase was dried over sodium sulphate and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel
eluting with dichloromethane:methanol 99:1 to yield the title product, 1.56g.
'HNMR (CDCI3, 400MHz) S: 0.00 (s, 6H), 0.78 (s, 9H), 0.93 (t, 3H), 3.29 (m,
2H),
3.71 (t, 2H), 4.72 (m, 2H), 4.94 (s, 2H). MS APCI+ m/z 405 [MH]+



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Preparation 155
N-f3-(tert-ButyldimethylsilLloxymethyl)-5-chloro-1-(2-ethoxyethyl)-1 H-
pyrazolof4,3-
dlpyrimidin-7-Ll]pyrimidin-4- la~ ine

~N
H3C0-") N N
~N
N\ N
H3C\ O N~
Si CI
H3C~ \ CH3
H3C CH3

Pyrimidin-4-ylamine (1.10g, 11.55mmol) was dissolved in tetrahydrofuran (30mL)
and the solution treated with sodium hexamethyldisilazide (2.12g, 11.55mmol)
and
stirred at room temperature for 20 minutes. The solution was then treated with
a
solution of the dichloro compound of preparation 154 (1.56g, 3.85mmol) in
tetrahydrofuran (10mL) and the reaction mixture stirred for 90 minutes at room
temperature. The reaction mixture was quenched with ammonium chloride solution
(100mL) and extracted with dichloromethane (200mL). The organic phase was
separated, dried over magnesium sulphate and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel eluting with
dichloromethane:methanol 97:3 to yield the title product, 830mg.

'HNMR (CDCI3, 400MHz) S: 0.00 (s, 6H), 0.77 (s, 9H), 1.08 (t, 3H), 3.54 (m,
4H),
4.63 (m, 2H), 4.90 (s, 2H), 8.33 (d, 1 H), 8.51 (d, 1 H), 8.77 (s, 1 H)
MS APCI+ m/z 464 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 155 using the appropriate
HNR'R2
amine.


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H3CN_Rl
N
N~
\ ~ N

H3C O N:
Si CI
H3C~ " CH3
H3C CH3
No. R' Data

'H NMR (CDCI3, 400MHz) 8: 0.18 (s, 6H), 0.93 (s,
156 9H), 1.21 (t, 3H), 3.65 (q, 2H), 3.97 (m, 2H), 4.80
N (m, 2H), 5.06 (m, 2H), 8.30 (m, 2H), 9.77 (m, 1 H),
10.17 (m, 1 H)

0 CH3 'H NMR (CDCI3, 400MHz) b: 0.20 (s, 6H), 0.95 (s,
157 ~ 9H), 1.25 (q, 3H), 3.65 (m, 2H), 3.95 (t, 2H), 4.02 (s,
N" \N
3H), 4.78 (t, 2H), 5.05 (s, 2H), 8.05 (d, 1 H), 8.50 (d,
1 H), 10.30 (s, 1 H). MS APCI+ m/z 494 [MH]+

CH3 'H NMR (CDCI3, 400MHz) b: 0.00 (s, 6H), 0.77 (s,
158 N~ N 9H), 1.13 (t, 3H), 2.48 (s, 3H), 3.53 (q, 2H), 3.80 (t,
2H), 4.62 (t, 2H), 4.89 (s, 2H), 8.03 (d, 1 H), 8.41 (d,
1 H), 10.12 (s, 1 H). MS ES+ m/z 478 [MH]+

CH3 'H NMR (CDCI3, 400MHz) 8: 0.10 (s, 6H), 0.95 (s,
N" \_N 9H), 1.38 (t, 3H), 2.42 (s, 6H), 3.65 (q, 2H), 3.95 (t,
159
2H), 4.79 (t, 2h), 5.10 (s,, 2H), 6.78 (s, 1 H), 10.18 (s,
3 1 H). MS APCI+ m/z 492 [MH]+

= Preparation 157 used the amine of preparation 6 as the HNR'R2 amine.

= Preparation 158 used 2-methylpyrimidin-4-ylamine (J. Het. Chem, 1987, 24,
1377-1380) as the HNR'R2 amine.


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Preparation 160
[5-Chloro-1 -(2-ethoxyethrLl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-
dlpyrimidin-3-
yllmethanol
N=~
H N
H3CO~ N

~N
N
N
HO N~
CI
The protected alcohol of preparation 155 (815mg, 1.76mmol) was dissolved in
tetrahydrofuran (40mL) and the solution treated with a 1 M solution of
tetrabutylammonium fluoride in tetrahydrofuran (8.63mL, 8.63mmol). The
reaction
mixture was stirred for 90 minutes at room temperature and was then treated
with
additional tetrabutylammonium fluoride solution (4.32mL) and stirred for
another
hour. The reaction mixture was diluted with water (50mL) and the aqueous
extracted
with ethyl acetate (3x5OmL). The combined organics were dried over magnesium
sulphate and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel eluting with dichloromethane:methanol 99:1 to
95:5 to
yield the title product, 1.25g.

'HNMR (CDC13, 400MHz) 8: 1.26 (t, 3H), 3.70 (m, 2H), 3.97 (m, 2H), 4.76 (m,
2H),
5.10 (s, 2H), 8.51 (d, 1 H), 8.72 (d, 1 H), 8.99 (s, 1 H). MS APCI+ m/z 350
[MH]+
The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 160 using the appropriate
protected
alcohol of preparations 156, 157, 158 and 159.
R1R2
N

f_O N
H3C N N
N~CI
OH
No. R' Data


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N 'H NMR (CDCI3, 400MHz) 8: 1.22 (t, 3H), 3.66 (m,
161 I ~ 2H) 3.98 (m, 2H), 4.80 (m, 2H), 5.08 (s, 2H), 8.34
N (m, 2H), 9.80 (m, 1 H), 10.22 (m, 1 H)

OCH3 'H NMR (DMSO-D6, 400MHz) 8: 1.10 (t, 3H), 3.58
162 N ~ (q, 2H), 3.83 (t, 2H), 3.90 (s, 3H), 4.65 (t, 2H), 4.78
N
(t, 2H), 5.48 (t, 1 H), 7.80 (d, 1 H), 8.58 (d, 1 H), 10.42
(s, I H). MS APCI- m/z 378 [M-H]"

CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.11 (t, 3H), 2.55
163 N \ N (s, 3H), 3.56 (q, 2H), 3.85, 4.69 (d, 2H), 4.79 (t, 2H),
~/ 5.33 (t, 1 H), 7.99 (d, 1 H), 8.60 (d, 1 H). MS ES+ m/z
364 [MH]+

CH3 'H NMR (DMSO-D6, 400MHz) b: 1.10 (m, 3H), 2.38
N" \ N (s, 6H), 3.43 (q, 2H), 3.75 (m, 2H), 4.55 (m, 2H),
164
k/ 4.70 (t, 2 H), 5.35 (t, 1 H), 6.98 (s, 1 H), 10.44 (s, 1 H).
CH3 MS APCI+ m/z 378 [MH]+

Preparation 165
5-Chloro-l-(2-ethoxyethyl)-7-(pyrazin-2-ylamino)-1 H-pyrazolof4,3-
a'lpyrimidine-3-
carbaldehyde
~N
H3C0 N ~ ~
~N N

\N
O N-
H CI
The alcohol of preparation 161 (251 mg, 0.72mmol) was dissolved in
dichloromethane (12mL) and the solution cooled to 0 C in an ice bath. 1,1,1-
Triacetoxy-l,l-dihydro-1,2-benziodoxol-3 (1 H)-one (Dess-Martin periodinane,
456mg, 1.08mmol) was added and the reaction mixture stirred at room
temperature
for 2 hours. The reaction mixture was treated with a saturated solution of
sodium
thiosulphate in water (7.8mL) and then with saturated sodium hydrogencarbonate


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solution (7.8mL) and ether (7.8mL). The mixture was stirred at room
temperature for
15 minutes, the organic phase separated and the aqueous extracted with
dichloromethane (x3). The organics were combined, dried over sodium sulphate
and
concentrated in vacuo. The crude product was purified by column chromatography
on silica gel eluting with dichloromethane:methanol 99:1 to yield the title
product,
200mg.

'HNMR (CDCI3, 400MHz) 8: 1.22 (t, 3H), 3.69 (m, 2H), 4.06 (m, 2H), 4.92 (m,
2H),
7.22 (m, 1 H), 8.32 (m, 1 H), 8.40 (m, 1 H), 9.77 (m, 1 H), 10.35 (m, 1 H)

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 165 using the appropriate
alcohol of
preparations 160, 162, 163, 164.
~
H3CR~N,R2
~N
N~ N
O N
H CI
No. R' Data

N~N 1H NMR (CDCI3, 400MHz) b: 1.23 (t, 3H), 3.72 (q, 2H),
166 I I 4.06 (t, 2H), 4.93 (m, 2H), 8.40 (d, 1 H), 8.75 (d, 1 H),
8.95 (s, 1 H), 10.37 (s, 1 H)
CH3
O 'H NMR (CDCI3, 400MHz) b: 1.25 (t, 3H), 3.70 (q, 2H),
167 Nl-~N 4.00 (m, 2H), 4.05 (s, 3H), 4.90 (t, 2H), 8.05 (d, 1 H),
8.55 (d, 1 H), 10.48 (m, 2H). MS APCI- m/z 376 [M-H]"
CH3 'H NMR (DMSO-D6, 400MHz) 6: 0.98 (t, 3H), 2.47 (s,
168 N" \ N 3H), 3.43 (q, 2H), 3.85 (t, 2H), 4.93 (t, 2H), 7.86 (d,
1 H), 8.48 (d, 1 H), 10.08 (s, 1 H). MS ES- m/z 360 [M-
H]"


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CH3 'H NMR (CDC13, 400MHz) b: 1.30 (m, 3H), 2.60 (s,

N" \ N 6H), 3.70 (t, 2H), 4.00 (t, 2H), 4.90 (m, 2H), 6.80 (m,
169
K/ I H), 10.30 (s, 1 H), 10.35 (s, I H). MS APCI- m/z 374
CH3 [M-H]-

Preparation 170
5-Chloro-1-(2-ethoxyethLl)-7-(pyrimidin-4-ylamino)-1 H-p razolo[4,3-
dlpyrimidine-3-
carboxylic acid

N
H3CO N
~N
N~ N
HO N--~
CI
0
The aldehyde of preparation 166 (220mg, 0.63mmol) was dissolved in tert-
butanol
(40mL) and the solution treated with a 2M solution of 2-methylbut-2-ene in
tetrahydrofuran (44mL). The solution was stirred at room temperature and then
treated dropwise with a solution of sodium chlorite (683mg, 7.59mmol) and
sodium
dihydrogen orthophosphate (699mg, 5.82mmol) in water (8mL) over 5 minutes. The
reaction mixture was stirred at room temperature for 30 minutes. Water (40mL)
and
dichloromethane (40mL) were added to the reaction mixture and the phases
separated. The aqueous layer was extracted with dichloromethane (2x4OmL) and
the aqueous was then acidified to pH 3 and extracted once more with
dichloromethane (2x4OmL). The organics were combined, dried over magnesium
sulphate and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel eluting with first dichloromethane:methanol 97:3
and
then dichloromethane:methanol:acetic acid 85:15:1 to yield the title product,
194mg.
'HNMR (CD30D, 400MHz) 6: 1.20 (t, 3H), 3.68 (m, 2H), 4.01 (t, 2H), 4.92 (t,
2H),
8.42 (m, I H), 8.68 (m, 1 H), 8.87 (m, 1 H). MS APCI+ m/z 364 [MH]+


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The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for preparation 170 using the appropriate
aidehyde
of preparations 165, 167, 168, 169.

H3C~O RN_Rz
N~ N
N

HO N::~CI
O

No. NR'R2 Data

171 N 'H NMR (CD3OD, 400MHz) 8: 1.20 (m, 3H), 3.65 (m,
2H), 3.99 (m, 2H), 4.96 (m, 2H), 8.36 (m, 1 H), 8.42
N (m, 1 H), 9.60 (m, 1 H). MS APCI+ m/z 364 [MH]+

172 O~CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.10 (m, 3H), 3.58
(q, 2H), 3.90 (m, 3H), 3.95 (s, 3H), 4.90 (t, 2H), 7.80
i\ N (d, 1 H), 8.58 (d, 1 H), 10.52 (m, 1 H). MS APCI- m/z
392 [M-H]-

173 CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.01 (t, 3H), 2.46 (s,
N" \ N 3H), 3.46 (q, 2H), 3.80 (t, 2H), 4.84 (t, 2H), 7.87 (d,
I H), 8.50 (d, 1 H). MS ES- m/z 376 [M-H]-

174 CH3 'H NMR (DMSO-D6, 400MHz) 8: 1.01 (t, 3H), 2.40 (s,
N" \ N 3H), 3.35 (s, 3H), 3.46 (q, 2H), 3.80 (t, 2H), 4.75 (t,
~-k~ 2H), 7.00 (d, I H),. MS ES- m/z 390 [M-H]-
CH3


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Preparation 175
Ethyl 5-chloro-l-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-p r~olo[4,3-

dJpyrimidine-3-carboxylate
H3C~\O N

N"N / ~ N CH3
O N-
H3C--/ O CI

The carboxylic acid of preparation 137 (565mg, 1.5mmol) was suspended in _1-
methyl-2-pyrrolidinone (5mL) and the solution treated with N-
ethyldiisopropylamine
(313 L, 1.8mmol) and N,N'-carbonyldiimidazole (364mg, 2.25mmol) and stirred
for
30 minutes at room temperature. The solution was treated with sodium ethoxide
(408mg, 6.Ommol) and the reaction mixture stirred for a further 30 minutes at
room
temperature. The reaction mixture was quenched with citric acid solution (5mL)
and
concentrated in vacuo. The residue was partitioned between dichloromethane
(100mL) and water (50mL) and the organic phase separated, dried over magnesium
sulphate and concentrated in vacuo. The residue was triturated with ethyl
acetate
(10mL) and dried in vacuo to yield the title product.

'H NMR (DMSO-D6, 400MHz) 8: 0.96 (t, 3H), 1.32 (t, 3H), 2.40 (s, 3H), 3.44 (q,
2H),
3.86 (t, 2H), 4.36 (q, 2H), 4.93 (t, 2H), 7.06 (m, 1 H), 7.87 (s, 1 H), 8.23
(d, 1 H),
MS APCI+ m/z 405 [MH]+


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Preparation 176
2-(Dimethylamino)ethyl 5-chloro-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-
ylamino)-1 H-
pyrazolo f4,3-dlpyrimidine-3-carboxylate

H3C~0 N

CH
N N 3
O N'\
CI
H3C-N O
CH3
The carboxylic acid of preparation 137 (282mg, 0.75mmol) was suspended in 1-
methyl-2-pyrrolidinone (2.5mL) and the solution treated with N-
ethyldiisopropylamine
(157 L, 0.9mmol) and N,N'-carbonyldiimidazole (182mg, 1.13mmol) and stirred at
room temperature for 30 minutes. The solution was treated with 2-
(dimethylamino)ethanol (309 L, 3.Ommol) and 4-(N,N-dimethylamino)pyridine

(12mg, 0.1 mmol) and the reaction mixture heated to 500C for 18 hours. The
reaction
mixture was concentrated in vacuo and the residue purified by column
chromatography on silica gel eluting with dichloromethane:methanol:0.88
ammonia
100:0:0 to 90:10:1 to yield the title product, 170mg.

'H NMR (CD3OD, 400MHz) 8: 1.08 (t, 3H), 2.40 (s, 6H), 2.45 (s, 3H), 2.84 (t,
2H),
3.60 (m, 2H), 3.98 (t, 2H), 4.57 (t, 2H), 5.01 (m, 2H), 6.98 (d, 1 H), 8.12
(m, 1 H).
MS APCI+ m/z 448 [MH]+


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Preparation 177
5-Chloro-1-(2-ethoxyethyl -7-(4-methylpyridin-2-ylamino)-1 H-pyrazolo[4,3-
djpyrimidine-3-carboxamide
I,--, 0 N
H3C
N
N~ / CH3
H2N N
CI
O

The carboxylic acid of preparation 137 (376mg, 1.0mmol) was added to a
solution of
N-[(dimethylamino)-1 H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-
methylmethanaminium hexafluorophosphate N-oxide (HATU, 380mg, 1.0mmol) and
N-ethyldiisopropylamine (1 mL, 5.6mmol) in N,N-dimethylformamide (15mL) The
mixture was then treated with a saturated solution of ammonia in
tetrahydrofuran

(600 L) and the reaction mixture stirred at room temperature for 48 hours. The
reaction mixture was concentrated in vacuo and the residue partitioned between
ethyl acetate (50mL) and water (50mL). The aqueous was extracted with ethyl
acetate (2x5OmL) and dichloromethane (50mL). The organics were combined, dried
over magnesium sulphate and concentrated in vacuo. The residue was purified by
column chromatography on silica gel eluting with dichloromethane:methanol
100:0 to
95:5 to yield the title product.

'H NMR (CDCI3, 400MHz) 8: 1.17 (t, 3H), 2.47 (s, 3H), 3.68 (m, 2H), 4.01 (t,
2H),
4.92 (m, 2H), 6.94 (m, 1 H), 8.08 (m, 1 H), 8.22 (m, 1 H). MS APCI+ m/z 376
[MH]+


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Preparation 178
5-Chloro-1 -(2-ethoxyethrl -7-(4-fluoro-3-methylphenylamino)-1H-pyrazolo[4 3-
dlpyrim idine-3-carboxamide

~
H3C0 N \ ~ F
N~ / ' N CH3
H2N N
O CI

The title compound was prepared by a method similar to that described for
preparation 177 using the carboxylic acid of preparation 152.

'H NMR (DMSO-D6, 400MHz) 8: 0.96 (t, 3H), 2.26 (s, 3H), 3.45 (q, 2H), 3.82 (m,
2H),
4.93 (m, 2H), 7.23 (t, 1 H), 7.50 (m, 2H), 7.64 (s, 1 H), 7.81 (s, 1 H), 9.37
(s, 1 H)
MS APCI+ m/z 393 [MH]+
Preparation 179
5-Chloro-1 -(2-eth oxyethyl)-7-(4-m ethyl pyridin-2-ylamino)-1 H-pyrazolo[4,3-
Opyri m i d i n e-3-ca rbo n itri l e

H3C0 N
~
N\ N/ N CH3

NC N- /\ CI

The amide of preparation 177 (140mg, 0.37mmol) was dissolved in a solution of
trifluoroacetic anhydride (53 L, 0.37mmol) and pyridine (59mg, 0.75mmol) in
tetrahydrofuran (5mL) and the reaction mixture stirred at room temperature for
18
hours. The reaction mixture was concentrated in vacuo and the residue purified
by
column chromatography on silica gel eluting with dichloromethane to yield the
title
product.

'H NMR (CDCI3, 400MHz) S: 1.09 (t, 3H), 2.40 (s, 3H), 3.66 (m, 2H), 3.91 (m,
2H),
5.00 (m, 2H), 6.85 (m, 1 H), 8.05 (m, 1 H), 8.08 (m, 1 H). MS APCI+ m/z 358
[MH]+


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Preparation 180
5-Chloro-l-(2-ethoxyethyl)-7-(4-fluoro-3-methylphenylamino)-1 H-pyrazolo[4,3-
dlpyrimid ine-3-carbon itrile

~
H3C~0 N \ F
N
N/I N CH3
NC N- /\
CI
The title compound was prepared by a method similar to that described for
preparation 179 using the amide of preparation 178.

'H NMR (CDCI3, 400MHz) 6: 1.19 (t, 3H), 2.32 (s, 3H), 3.68 (q, 2H), 4.04 (m,
2H),
4.80 (m, 2H), 7.05 (t, 1 H), 7.56 (m, 2H), 9.37 (s, 1 H). MS ES+ m/z 397
[MNa]+

Preparation 181
5-Chloro-l-(2-ethoxyethyl)-N-hydroxy-7-(4-methylp ridin-2-ylamino)-1 H-
pyrazolo[4,3-djpyrimidine-3-carboxamidine

N-
H3C0~ N \ ~
ZN
N N CH3
N_ N-\
HO NH2 CI

The nitrile of preparation 179 (100mg, 0.28mmol) was dissolved in a solution
of
hydroxylamine (23mg, 0.34mmol) in ethanol (2mL) and the solution treated with
a
5M aqueous solution of sodium hydroxide (68 L, 0.34mmol). The reaction mixture
was stirred at 50 C for 18 hours and then concentrated in vacuo to yield the
title
product.

'H NMR (DMSO-D6, 400MHz) 8: 1.02 (m, 3H), 2.37 (s, 3H), 3.50 (m, 2H), 3.85 (m,
2H), 4.84 (m, 2H), 6.96 (m, 1 H), 8.16 (m, 1 H), 8.20 (m, 1 H). MS ES+ m/z 358
[MH]+


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Preparation 182
5-Chloro-1 -(2-ethoxyethyl)-7-(4-fluoro-3-methlyphenylamino)-N-h droxy-1H-
pyrazolo[4,3-d]pyrimidine-3-carboxamidine
~
H3CO N \ F
N
N ~/ ~ CH3
N

HO NH2 CI

The title compound was prepared by a method similar to that described for
preparation 181 using the nitrile of preparation 180.

'H NMR (DMSO-D6, 400MHz) 5: 0.95 (t, 3H), 2.26 (s, 3H), 3.44 (d, 2H), 3.79 (m,
2H),
4.88 (m, 2H), 7.21 (t, 1 H), 7.50 (m, 2H), 9.30 (m, 1 H), 9.95 (s, 1 H)
MS ES- m/z 406 [M-H]-
Preparation 183
3-[5-Chloro-1-(2-ethoxyethyl)-7-(4-methypyridin-2-ylamino)-1 H-pyrazolo[4,3-
dlpyrimidin-3-yl1-2H-1,2,4-oxadiazol-5-one

H3C~0 N
N
N ~ CH3
N
-
N- N
~ O ~NH CI
O

The product of preparation 181 (109mg, 0.28mmol) was dissolved in a solution
of
N,N'-carbonyldiimidazole (49mg, 0.30mmol) in N,N-dimethylformamide (2mL) and
the reaction mixture stirred at 80 C for 2 hours. The reaction mixture was
concentrated in vacuo and the residue triturated with acetone (3mL), filtered
and
recrystalised from acetonitrile to yield the title product.

'H NMR (DMSO-D6, 400MHz) 8: 1.00 (t, 3H), 2.39 (s, 3H), 3.47 (m, 2H), 3.87 (t,
2H),
4.95 (t, 2H), 6.98 (d, 1 H), 7.87 (s, 1 H), 8.17 (m, 1 H). MS APCI+ m/z 417
[MH]+


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Preparation 184
3-r5-Chloro-1 -(2-ethoxrLethyl)-7-(4-fluoro-3-meth ly phenylamino -1 H-p
ra~olo[4,3-
dl pyrimidin-3-yl]-2H-1;2,4-oxadiazol-5-one

~
H3C~O N H ~ ~ F
\ N
N N CH3
-
N- N
~ O "NH CI
O
-
The title compound was prepared by a method similar to that described for
preparation 183 using the product of preparation 182.

'H NMR (DMSO-D6, 400MHz) 8: 0.96 (t, 3H), 2.27 (s, 3H), 3.45 (m, 2H), 3.83 (m,
2H), 4.97 (m, 2H), 7.24 (t, 1 H), 7.50 (m, 2H), 9.40 (s, I H). MS APCI+ m/z
434 [MH]+
Preparation 185
N-[5-Chloro-l-(2-ethoxyethyl)-3-(2H-tetrazol-5-yl)-1 H-pyrazolo[4,3-
c/]pyrimidin-7-LrI]-
(4-meth,r Ip ridy in-2- rI amine

N-
H3CO N ~ ~

CH
N~ N 3
N N
CI
N\N~N

H
The nitrile of preparation 179 (1 00mg, 0.28mmol) was added to a solution of
azidotributyltin (1 04mg, 0.32mmol) in dioxane (3mL) and the reaction mixture
heated
to reflux for 18 hours. The reaction mixture was treated with further
azidotributyltin
(104mg, 0.32mmol) and the reaction mixture heated to reflux for a further 18
hours.
The reaction mixture was diluted with a 2M solution of hydrochloric acid in
ether
(20mL) and the mixture stirred at room temperature for 30 minutes. The
reaction


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mixture was concentrated in vacuo and the residue adsorbed onto silica and
purified
by column chromatography on silica gel eluting with
dichloromethane:methanol:acetic acid 100:0:0 to 90:10:1 to yield the title
product.

'H NMR (CD3OD, 400MHz) 8: 1.11 (t, 3H), 2.57 (s, 3H), 3.64 (q, 2H), 4.05 (t,
2H),
5.09 (t, 2H), 7.25 (d, 1 H), 7.90 (s, 1 H), 8.35 (d, I H). MS APCI+ m/z 401
[MH]+
Preparation 186
N-[5-Chloro-1-(2-ethoxyethyl)-7-(4-methylpyridin-2- larmino)-1 H-pyrazolo[4,3-
dlpyrimidine-3-carbonLllmethanesulfonamide
H3C0 N \
N N CH3
O. N N
S\O O CI
H3C
The carboxylic acid of preparation 137 (1.0g, 2.70mmol), methanesulphonamide
(330mg, 3.5mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(660mg, 3.5mmol) and 4-dimethylaminopyridine (390mg, 3.5mmol) were dissolved
in
N,N-dimethylformamide (10mL) and the reaction mixture stirred at room
temperature
for 60 hours. Additional methanesulphonamide (165mg, 1.7mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 1.7mmol) and 4-
dimethylaminopyridine (195 1.7mmol) were added and the reaction mixture
stirred
for a further 20 hours. Further methanesulphonamide (165 1.7mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 1.7mmol) and 4-
dimethylaminopyridine (195 1.7mmol) were added and the reaction mixture
stirred
for a final 18 hours. The reaction mixture was concentrated in vacuo and the
residue
partitioned between dichloromethane (25mL) and water (25mL). The organic phase
was separated, washed with water (2x25mL), dried over magnesium sulphate and
concentrated in vacuo. The residue was purified by column chromatography on
silica
gel eluting with dichloromethane:methanol:acetic acid 100:0:0 to 96:3.5:0.5.
The


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crude product was triturated in warm ethyl acetate (10mL) to yield the title
product,
290mg.

'H NMR (DMSO-D6, 400MHz) b: 0.95 (t, 3H), 2.40 (s, 3H), 3.40 (s, 3H), 3.45 (d,
2H),
3.85 (m, 2H), 4.95 (m, 2H), 7.15 (d, 1 H), 7.85 (s, 1 H), 8.25 (d, 1 H)
MS ES- m/z 452 [M-H]"

Preparation 187
3-(Methoxycarbonyl)-1-[(2S)-2-methoxypropyl]-4-nitro-1 H-pyrazole-5-carboxylic
acid
H3C
H3C, 0 O~~ 0
~N
N~ ~ OH

O N=0
/ O O
H3C
Diisopropyl azodicarboxylate (14.9mL, 76mmol) was added dropwise to a solution
of
dimethyl 4-nitropyrazole-3,5-dicarboxylate (15.73g, 69mmol), (S)-(+)-2-
methoxypropanol (6.81g, 76mmol) and triphenylphosphine (19.9g, 76mmol) in
tetrahydrofuran (220mL) with stirring under nitrogen, keeping the reaction
temperature between 0 C and 10 C by cooling in an ice bath. Once addition was
complete the reaction was allowed to stir at room temperature for 18 hours.
The
reaction mixture was concentrated under reduced pressure and the residual oil
re-
dissolved in methanol (200mL). Potassium hydroxide (3.88g, 69mmol) was added
and the reaction was allowed to stir at room temperature for 18 hours. The
mixture
was concentrated under reduced pressure and the residue suspended in water
(50mL), and washed with dichloromethane (2x100mL). The aqueous solution was
acidified to pH 1 using concentrated hydrochloric acid, and then extracted
with
dichloromethane (3x100mL). The combined organic extracts from extraction of
the
acidic solution were evaporated to dryness;-then taken up in saturated aqueous
sodium bicarbonate solution (100mI). The aqueous solution was washed
sequentially with dichloromethane (100mL), and ethyl acetate (2x100m1), then
acidified to pH1 with concentrated hydrochloric acid and extracted with ethyl
acetate


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(3x100ml). The combined organic extracts from extraction of the acidic
solution were
dried over magnesium sulphate and concentrated under reduced pressure to
afford
the title compound as a yellow oil.

'H NMR (DMSO-D6, 400MHz) 8: 1.05 (d, 3H), 3.10 (s, 3H), 3.70 (m, 1 H), 3.85
(d,
3H), 4.45-4.70 (m, 2H).
MS APCI+ m/z 288 [MH]+

Preparation 188
2-(Cyclobutyloxy)ethanol
ff O_~_~OH

Butyl lithium (2.5M in hexanes, 61 mL, 0.152mol) was added dropwise to an ice-
cold
solution of cyclobutanol (10g, 0.139mo1) in tetrahydrofuran (250mL) so as to
maintain the reaction temperature below 10 C. The mixture was then stirred for
a
further 2 hours at 5-10 C, and a solution of 1,3,2-dioxathiolane 2,2-dioxide
(1 8.90g,
0.152mol) in tetrahydrofuran (50mL) was added dropwise so as to maintain the

reaction temperature below 15 C. Once addition was complete the reaction was
stirred for a further 3 hours at room temperature, water (3mL) followed by
concentrated sulphuric acid (7.5mL) then added and the reaction stirred for an
additional 18 hours. The reaction was carefully neutralised by the addition of
solid
sodium carbonate and sodium bicarbonate, and the mixture concentrated under
reduced pressure at room temperature. The residue was diluted with water,
saturated with sodium chloride added until saturation was achieved and the
solution
then extracted with ethyl acetate (4x100mL). The combined organic extracts
were
dried over magnesium sulphate and evaporated under,reduced pressure at room
temperature. The residual orange oil was purified by Kugelrohr distillation to
afford

the title compound, 7.7g. bp 70-80 C at 10mmHg.

'H NMR (CDCI3,400 MHz) S: 1.38-1:57 (m, 1 H), 1.63 (m, 1 H), 1.80-1.98 (m,
2H),
2.06-2.15 (m, 2H), 3.40 (t, 2H), 3.65 (t, 2H), 3.95 (m, 1 H).

Preparation 189


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1-[2-(CyclobutyloxY)ethyll-3-(methoxycarbonyl)-4-nitro-1H-pyrazole-5-carbox
lic acid

;1
O

O
N ~ OH
0 N-O
/ O O
H3C

The title compound was obtained as a white solid from the alcohol from
preparation
188 and dimethyl 4-nitropyrazole-3,5-dicarboxylate following a similar
procedure to
that described in preparation 187.

1 H NMR (CDCI3, 400MHz) 8: 1.38-1.50 (m, 1 H), 1.62 (m, 1 H), 1.70-1..81 (m,
2H),
2.10 (m, 2H), 3.76 (m, 2H), 3.90 (m, 4H), 4.78 (t, 2H), 9.68 (br s, 1 H).
MS ES+ m/z 331 [MNH4]+
Preparation 190
2-(2,2-DifluoroethoxY ethanol
F
Tetra-butyl ammonium bromide (1.96g, 6.08mmol) was added portionwise to a
solution of 2,2-difluoroethanol (25g, 304.9mmol) in triethylamine (45mL,
322.9mmol)
and the mixture stirred for 5 minutes. Ethylene carbonate (29.53g, 335.3mmol)
was

added and the reaction mixture was heated at 100 C for 18 hours. The cooled
mixture was then distilled under reduced pressure, and the distillate
containing the
desired product was redistilled at atmospheric pressure to provide the title
compound as a yellow liquid, 4.95g (b.p.127-128 C).

'H NMR (CDCI3 , 400MHz) 8: 2.04 (br s, 1 H), 3.65 (m, 2H), 3.72 (m, 4H), 5.70-
6.02
(m, 1 H).

Preparation 191


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1-[2-(2,2-Difluoroethoxy)ethyll-3-(methoxycarbon rLl)-4-nitro-1 H-pyrazole-5-
carboxylic

acid
FO

1F O
N\ OH
O N=O
/O O
H3C

The title compound was obtained as a white solid, from the alcohol from
preparation
190 and dimethyl 4-nitropyrazole-3,5-dicarboxylate, using a similar procedure
to that
described in preparation 187.

'H NMR (CDCI3,400MHz) S: 3.61 (m, 2H), 3.92 (m, 5H), 4.80 (t, 2H), 5.60-5.88
(m,
1 H).
MS ES+ m/z 324 [MH]+
Preparation 192
3-(Methoxycarbonyl)-4-nitro-l-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazole-5-
carboxylic acid

F~O
O
F F
NN OH
\
N"O
H3c`o o
O
A solution of diisopropyl azodicarboxylate (71.9mL, 366mmol) in
tetrahydrofuran
(80mL) was added dropwise to a solution of dimethyl 4-nitropyrazole-3,5-
dicarboxylate (60g, 260mmol), 2,2,2-trifluoroethoxyethanol (Journal of
Fluorine
Chemistry (1992), 59(3), 387-96), (45.2g, 314mmol) and triphenylphosphine
(96.15g, 366mmol) in tetrahydrofuran (650mL) with stirring under nitrogen,
maintaining the reaction temperature between 0 C and 1 0 C by cooling in an
ice


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bath. After the addition was complete, the mixture was allowed to warm to room
temperature and stirred for 2 days. The solvent was removed under reduced
pressure and the residue was dissolved in methanol (800mL) and cooled to 0 C.
A
solution of potassium hydroxide (16.16g, 288mmol) in methanol (200mL) was
added

at 0 C and the reaction was allowed to warm to room temperature and stirred
for 16
hours. The solvent was removed under reduced pressure and the residue was
partitioned between water (600mL) and ethyl acetate (600mL). The aqueous layer
was washed with ethyl acetate (2 x 200mL) and the aqueous phase then acidified
with hydrochloric acid to pH1. The aqueous solution was extracted with ethyl

acetate (3 x 400mL), the combined extracts were dried over sodium sulphate and
concentrated under reduced pressure to afford a colourless solid (52.86g,
59%).
The product was a mixture of 3-methoxycarbonyl-4-nitro-l-(2,2,2-
trifluoroethoxy)ethylpyrazole-5-carboxylic acid (major) and 5-methoxycarbonyl-
4-
nitro-l-(2,2,2-trifluoroethoxy)ethylpyrazole-3-carboxylic acid (minor) and was
used
directly for the next step.

'H NMR (CDC13,400MHz) 8: 3.77 (q, 2H), 3.93 (s, 3H), 4.00 (t, 2H), 4.84 (t,
2H).
Preparation 193
2-(3,3,3-Trifluoropropoxy)ethanol
F
F~I C~~\OH
F
n-Butyl lithium (39mL, 2.5M in hexanes, 97.5mmol) was added dropwise to an ice-

cooled solution of 3,3,3-trifluoropropan-l-ol (10g, 87.7mmol) in
tetrahydrofuran
(130mL), so as to maintain the temperature below 5 C, and once addition was
complete the reaction was stirred for a further hour at 0 C.
A solution of 1,3,2-dioxathiolane 2,2-dioxide (11.97g, 96.5mmol) in
tetrahydrofuran
(35mL) was then added dropwise-so as to maintain the internal temperature
below
5 C, and once addition was complete the reaction was stirred at room
temperature
for 18 hours. Water (2mL) followed by concentrated sulphuric acid (5mL) were
added and the reaction stirred for a further 6 hours at room temperature. The


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mixture was neutralised by the addition of sodium carbonate, then diluted with
water
(20mL) and the resulting solid filtered off and washed with ethyl acetate. The
filtrate
was concentrated under reduced pressure and the residue suspended in brine and
extracted with ethyl acetate (3x). The combined organic extracts were dried
over
magnesium sulphate and evaporated under reduced pressure. The residual gum
was distilled under high vacuum to afford the title compound as a colouriess
liquid,
6.75g (b.p.57-80 C).

'H NMR (CDCI3,400 MHz) 8: 2.38 (m, 2H), 2.57 (m, 2H), 3.69 (m, 4H).
Preparation 194
3-(MethoxycarbonYI)-4-nitro-1-[2-(3,3,3-trifluoropropoxY)ethYI]-1H-pYrazole-5-
carboxylic acid
F
F,)___/-O

O
F
iN OH
N:O
H3C~0 O

O
The title compound was obtained as a white solid, from the alcohol from
preparation
193 and dimethyl 4-nitropyrazole-3,5-dicarboxylate, following the procedure
described in preparation 187.

'H NMR (CDCI3,400 MHz) 8: 2.39 (m, 2H), 3.54 (t, 2H), 3.78 (m, 2H), 3.80 (s,
3H),
4.69 (t, 2H).
MS ES+ m/z 356 [MH]+
Preparation 195
2-(3-Fluoropropoxy)ethanol
F~O"I'--"OH


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The title compound was obtained in 71 % yield, from 3-fluoropropan-1-ol and
1,3,2-
dioxathiolane 2,2-dioxide, following a similar procedure to that described in
preparation 193.

'H NMR (CDC13,400 MHz) 8: 1.96 (m, 2H), 2.10 (bs, 1 H), 3.58 (t, 2H), 3.62 (t,
2H),
3.75 (t, 2H), 4.50 (dd, 1 H), 4.62 (dd, I H).

Preparation 196
1-[2-(3-Fluoropropoxy)ethyl1-3-(methoxycarbon rl -4-nitro-1 H-pyrazole-5-
carboxylic
acid

FO
iN I OH
+- O
H3C N
\ ~-
O
The title compound was obtained in 92% yield from dimethyl 4-nitropyrazole-3,5-

dicarboxylate and the alcohol from preparation 195 following the procedure
described in preparation 187.

'H NMR (CDCI3,400 MHz) 8: 1.81-1.95 (m, 2H), 3.56 (t, 2H), 3.83 (t, 2H), 3.97
(s,
3H), 4.38 (m, 1 H), 4.48 (m, 1 H), 4.82 (m, 2H).
MS ES+ m/z 320 [MH]+
Preparation 197
Methyl 5-(aminocarbonyl)-1-[(2S)-2-methoxypropyl]-4-nitro-1 H-pyrazole-3-
carbox, ly ate
H3
H3C'0 0
N~ / NH2

O N=0
/ O O
H3C


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Oxalyl chloride (6.83mL, 78.3mmol) was added to a solution of the acid from
preparation 187 (15g, 52.2mmol) in dichloromethane (250mL) at 0 C. N,N-
Dimethylformamide (0.15mL) was added and the mixture was allowed to stir for
18
hours at room temperature. Tlc analysis (dichloromethane:methanol:0.88
ammonia,
95:5:1) showed starting material remaining, so additional oxalyl chloride
(0.91 mL,
10mmol) was added dropwise and the reaction stirred for a further 18 hours at
room
temperature. The solution was evaporated under reduced pressure and the
residue
was dissolved in tetrahydrofuran (250mL). The solution was cooled to 0 C, 0.88
ammonia (20mL) added dropwise, and once addition was complete, the reaction
was stirred at room temperature for 1 hour. The reaction was concentrated
under
reduced pressure and the residue partitioned between dichloromethane (200mL)
and water (50mL) and the layers separated. The aqueous solution was extracted
with further dichloromethane (200mL), the organic solutions combined, dried
over
magnesium sulphate and evaporated under reduced pressure to give the title
compound as a white solid.

'H NMR (DMSO-D6, 400MHz) b: 1.25 (d, 3H), 3.30 (s, 3H), 3.85 (m, 1 H), 4.00
(s,
3H), 4.40-4.50 (m, 2H), 6.20 (s, 1 H), 7.50 (s, 1 H).
MS APCI+m/z 287 [MH]+
Preparation 198
Methyl5-(aminocarbonyl)-1-[2-(c cly obutyloxy)eth~rl]-4-nitro-lH-pyrazole-3-
carbox ly ate

O

O
N~ NH2
O N=-O
/ O O
H3C

A solution of oxalyl chloride (6.71 mL, 76.7mmol) in dichloromethane (30mL)
was
added slowly to a solution of the acid from preparation 189 (20g, 63.9mmol)
and


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N,N-dimethylformamide (0.28mL) in dichloromethane (140mL) with stirring and
the
mixture stirred at room temperature for 2 hours. The mixture was concentrated
under reduced pressure and the residue azeotroped with dichloromethane
(4x200mL) to give an orange oil that was dried in vacuo. The residue was
dissolved

in tetrahydrofuran (170mL), the solution cooled to -78 C and concentrated
aqueous
ammonia (23.2 mL, 0.42mol) was added dropwise. Once addition was complete, the
reaction was stirred for a further 2 hours at -78 C. The reaction was quenched
by
the addition of excess 6N hydrochloric acid (17mL) at -78 C. The mixture was
allowed to warm to room temperature and the tetrahydrofuran was removed under
reduced pressure. The resulting aqueous suspension was filtered, and the
resulting
solid washed with saturated sodium bicarbonate solution (2x5OmL). The solid
was
then washed with water until the filtrate was neutral, then dried in vacuo.
The solid was stirred for 1 hour in a solution of ether:methanol (10:1 by
volume, at
5mL/g solid), then filtered and dried. The solid was then stirred in a
solution of
ether:methanol (5:1 by volume, 5mL/g solid), filtered and dried in vacuo to
afford the
title compound, 10.34g.

1H NMR (CDCI3, 400 MHz) b: 1.41-1.82 (m, 4H), 2.17 (m, 2H), 3.74 (t, 2H), 3.86
(m,
1 H), 3.97 (s, 3H), 4.60 (t, 2H), 6.06 (br s, 1 H), 7.54 (br s, 1 H).
MS ES+ m/z 330 [MNH4]+

Preparation 199
Methyl 5-(aminocarbonyl -4-nitro-l-[2-(2,2,2-trifluoroethoxy)eth IL]-1 H-
pyrazole-3-
carboxylate
0
F-7C '-~ O
F F N N NH2
\
N:O
H3~\ o o
O
The carboxylic acid from preparation 192 (70.0g, 204mmol) was dissolved in a
mixture of dichloromethane (1000mL) and N,N-dimethylformamide (1 mL) under
nitrogen at 20 C. Oxalyl chloride (25mL, 366mmol) was added dropwise with


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stirring. The mixture was stirred for 16 hours then concentrated under reduced
pressure. Three portions of dichloromethane (200mL) were added and evaporated
sequentially to remove excess oxalyl chloride. The residue was dissolved in
tetrahydrofuran (1000mL) and cooled to -78 C. Concentrated aqueous 0.88

ammonia (70mL) was added dropwise maintaining the mixture at -78 C. After the
addition was complete the mixture was stirred for 1 hour, and then an excess
of
hydrochloric acid was added at -78 C (to give pH1). The mixture was allowed to
warm to room temperature and the solvent was removed under reduced pressure.
The resulting cream-coloured solid was collected by filtration and washed with
water

(3 x 100mL) to give a colouriess solid (47.01 g). Trituration of the solid
with a
mixture of diethyl ether and methanol (20:1, 20mL/g) gave the title compound
as a
colourless solid (40.0g, 61%).
'H NMR (CDCI3, 400 MHz) 3.78 (q, 2H), 3.95 (s, 3H), 3.98 (t, 2H), 4.76 (t,
2H), 5.91
(br s, 1 H), 7.03 (br s, 1 H).
Preparation 200
Methyl 5-(aminocarbon rLl)-1-[2-(2,2-difluoroethoxy)ethyl]-4-nitro-1 H-
pyrazole-3-
carboxylate
O
F-C "-~ O
F N N NH2
\
N:O
H3C\ 0 O

O
The title compound was obtained as a white solid from the compound from
preparation 191, following the procedure described in preparation 199.
'H NMR (DMSO-d6, 400 MHz) 3.63 (m, 2H), 3.85 (m, 5H), 4.39 (t, 2H), 5.84-6.19
(m,
1 H), 8.38 (s, 1 H), 8.45 (s, 1 H).
MS ES+ m/z 323 [MH]+
Preparation 201
Methyl5-(aminocarbonyl)-4-nitro-l-[2-(3,3,3-trifluoropropoxy)eth 1~1-1H-
pyrazole-3-
carboxylate


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F
F,)___,//-O
0
F

iN NH2
+" O
H3C N
\0 0-
O

The title compound was obtained as a white solid from the acid from
preparation
194, following a similar procedure to that described in preparation 199.
'H NMR (DMSO-d6, 400 MHz) 2.43 (m, 2H), 2.55 (m, 2H), 3.76 (t, 2H), 3.94 (s,
3H),
4.28 (m, 2H), 8.38 (m, 2H).
MS ES- m/z 353 [M-H]-
Preparation 202
Methyl 5-(aminocarbonyl)-1-[2-(3-fluoropropoxy)ethyll-4-nitro-1 H-pyrazole-3-
carboxylate
/11---/-O
O
F

iN NH2
NO
H3C~0 OI_

O
The title compound was obtained as a white solid from the acid from
preparation
196, following a similar procedure to that described in preparation 199.

'H NMR (CDCI3,400 MHz) 8: 1.83-1.99 (m, 2H), 3.58 (t, 2H), 3.84 (t, 2H), 3.98
(s,
3H), 4.40 (m, 1 H), 4.54 (m, 1 H), 4.70 (t, 2H).
MS APCI+ 319 [MH]+
Preparation 203
Methyl 4-amino-5-(aminocarbonyl)-1-f (2S)-2-methoxypropLll-1 H-pyrazole-3-
carboxylate


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H3C
H3C'0 0
VN N NH2
O
O
H3C

A solution of the compound from preparation 197 (7.1 g, 25mmol) and palladium
hydroxide (500mg) in methanol (200mL) was warmed to gentle reflux, and then
ammonium formate (5.95g, 94mmol) added portionwise (care exotherm). Once the
addition was complete the reaction was stirred under reflux for 18 hours under
nitrogen. The cooled mixture was filtered through wet Arbocel , and the
filtrate
evaporated under reduced pressure to give the title compound as a yellow oil,
5.4g.
'H NMR (CDCI3, 400 MHz) 8: 1.25 (d, 3H), 3.30 (s, 3H), 3.90 (m, 4H), 4.21-4.50
(m,
2H).
MS APCI+ m/z 279 [MNa]+

Preparation 204
Methyl 4-amino-5-(aminocarbonyl)-1-[2-(cyclobutyloxy)ethLl]-1 H-pyrazole-3-
carboxylate

O

O
N\ NH2
O NH2
O
H3C
A solution of the compound from preparation 198 (10.34g, 33mmol) in methanol
(400mL) was hydrogenated over 10% palladium on charcoal (Degussa 101 type,
2.1 g) at 50psi Hz and 50 C for 5 hours. The solution was filtered through
Arbocel


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filter aid. The filtrate was concentrated under reduced pressure, to afford
the title
compound as a colourless liquid, 9.32g.

'H NMR (CDCI3, 400MHz) 8: 1.39-1.52 (m, 1H), 1.60-1.80 (m, 3H), 2.12 (m, 2H),
3.80 (t, 2H), 3.90 (m, 4H), 4.32-4.70 (m, 2H).
MS ES+ m/z 305 [MNa]+
Preparation 205
Methyl 4-amino-5-(aminocarbonyl)-1-[2-(2,2-difluoroethoxy)ethyll-1 H-pyrazole-
3-
carboxylate
O
F4- \----iN O

F NH2
H3C\ NH2
O
O
A mixture of the compound from preparation 200 (4.83g, 15mmol) and 10%
palladium on charcoal (1.2g) in methanol (250mL) was hydrogenated at 3 Bar of
hydrogen arid room temperature for 24 hours. The mixture was warmed to 50 C,
filtered through Arbocel , washing through with warm methanol (500mL). The
filtrate
was concentrated under reduced pressure, and the residue azeotroped with
acetonitrile to afford the title compound as a white solid, 3.8g.

'H NMR (CDCI3, 400MHz) 6: 3.68 (m, 2H), 3.91 (s, 3H), 4.03 (t, 2H), 4.61 (t,
2H),
5.61-5.96 (m, 1 H), 6.20-6.39 (br s, 2H).
MS ES+ m/z 293 [MH]+
Preparation 206
Methyl 4-amino-5-(aminocarbon rl -1-[2-(2,2,2-trifluoroethoxy)ethyl -[2-
(rLrazole-3-
carboxylate
O/-
iN NH2
F F H3C\ NH2
O
0


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A solution of the compound from preparation 199 (40.0g, 11 8mmol) in methanol
(640mL) was hydrogenated over 10% palladium on charcoal (10.0g) at 3 bar and
50 C for 3 hours. The hot solution was filtered through Arbocel filter aid
and the
filter cake was washed with dichloromethane. The filtrate was concentrated
under
reduced pressure. The residue was kept under vacuum overnight at room
temperature to provide the title product as an off-white solid, (34.2g, 94%).

'H NMR (CDCI3, 400MHz) b: 3.80 (q, 2H), 3.91 (s, 3H), 4.07 (t, 2H), 4.63 (t,
2H),
6.29 (br s, 2H).
Preparation 207
Methyl 4-amino-5-(aminocarbonyl)-1-[2-(3,3,3-trifluoropropoxY)eth I~r 1-1 H-
pyrazole-3-
carboxylate
F
F~~O
F O
iN
NH2
H3C` NH2
O
O
The title compound was obtained as an off-white solid, from the compound from
preparation 201 following a similar procedure to that described in preparation
205.

'H NMR (DMSO-d6, 400MHz) 8: 2.41 (m, 2H), 3.52 (t, 2H), 3.68 (t, 2H), 3.74 (s,
3H),
4.49 (t, 2H), 5.09 (s, 2H), 7.40 (s, 2H).
MS APCI+ m/z 325 [MH]+
Preparation 208
Methyl 4-amino-5-(aminocarbonLl)-1-[2-(3-fluoropropoxy)ethyll-1 H-pyrazole-3-
carboxylate
/'-O
Fi/~' O
NN I NH2
\
H3C\ NH2
O
0


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The title compound was prepared in quantitative yield from the compound from
preparation 202, following the procedure described in preparation 206.

'H NMR (CDCI3, 400 MHz) 8: 1.83-1.99 (m, 2H), 3.61 (t, 2H), 3.95 (m, 5H), 4.38
(m,
1 H), 4.50 (m, I H), 4.58 (m, 2H).

Preparation 209
Methyl 1-[(2S)-2-methoxypropyll-5,7-dioxo-4,5,6, 7-tetrahydro-1 H-pyrazolo[4,3-

c.~= pyrimidine-3-carboxylate

H3C
O
H3C-O)---~

j I NH H3CN0
H O
O
A mixture of the amine from preparation 203 (2.7g, 9.7mmol) and 1,1'-
carbonyldiimidazole (1.89g, 11.7mmol) in N,N-dimethylformamide (80mL) was
stirred at room temperature for 1 hour. The mixture was concentrated under
reduced pressure and the residue dissolved in acetone. The mixture was
sonicated
for 30 minutes, and the resulting precipitate filtered off and dried. The
filtrate was
sonicated again, the precipitate was filtered, dried and combined to afford
the title
compound, 740mg.

'H NMR (DMSO-d6, 400MHz) 8: 1.05 (m, 3H), 3.15 (s, 3H), 3.75-3.85 (m, 1 H),
3.88
(s, 3H), 4.40, 4.60 (2xm, 2H).
MS APCI+ 305 [MNa]+
Preparation 210


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Methyl 1-[2-(cyclobutyloxy)ethyl]-5,7-dioxo-4,5,6,7-tetrahydro-1 H-
pyrazolo[4,3-
dlpyrimidine-3-carboxylate

0-O
O

NH
NN I H O
\ ~
H3C~0
O
A solution of the amide from preparation 204 (9.32g, 33mmol) in acetonitrile
(70mL)
was added dropwise to a refluxing solution of 1,1'-carbonyldiimidazole
(13.38g,
82.5mmol) in acetonitrile (230mL). The reaction was then stirred for a further
18
hours under reflux, and then cooled to 0 C. The resulting yellow precipitate
was
filtered off, washed with ice-cold acetonitrile and dried in vacuo to afford
the title
compound, 7.28g.

'H NMR (CDCI3, 400MHz) 8: 1.26-1.40 (m, 1 H), 1.54 (m, 1 H), 1.63 (m, 2H),
2.01 (m,
1 H), 3.63 (t, 2H), 3.81 (m, 4H), 4.59 (t, 2H), 11.78 (br s, I H), 11.38 (br
s, 1 H).
MS ES" m/z 307 [M-H]-
Preparation 211
Methyl 1-r2-(2,2-difluoroethoxy)ethyl]-5,7-dioxo-4,5,6,7-tetrahydro-1 H-
pyrazolo[4,3-
djpyrimidine-3-carboxylate
F ~
~O
iN NH
F

H O
H3C\0
O
A solution of 1,1'-carbonyldiimidazole (3.16g, 19.5mmol) in acetonitrile
(60mL) was
added portionwise over 3 hours to a solution of the compound from preparation
205
(3.8g, 13.Ommol) in acetonitrile (150mL) stirring under reflux. The reaction
was then
stirred under reflux for a further 3 hours and allowd to cool. The reaction
mixture was
concentrated under reduced pressure and the residue triturated with water, the


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resulting solid filtered off, washed with water and dried in vacuo to afford
the title
compound as a pale grey solid, 3.17g.

'H NMR (DMSO-d6, 400MHz) S: 3.61 (m, 2H), 3.79 (s, 3H), 3.90 (t, 2H), 3.64 (t,
2H),
5.99 (m, 1 H), 10.78 (bs, 1 H), 11.35 (bs, 1 H).
MS ES+ m/z 318 [MH]+
Preparation 212
Methyl 5,7-dioxo-l-[2-(2,2,2-trifluoroethoxy)ethyll-4,5,6,7-tetrahydro-1 H-
pyrazolo[4,3-d]pyrimidine-3-carbox I~
~ O
O
F- NN NH
F F

H O
H3C\0
O
A solution of the amine from preparation 206 (21.7g, 70.Ommol) in acetonitrile
(150mL) was added dropwise over 2 hours to a stirred solution of 1,1'-
carbonyldiimidazole (17.02g, 105mmol) in refluxing acetonitrile (850mL) under
nitrogen. The mixture was heated under reflux for 2 hours, cooled and the
solvent
was removed under reduced pressure. The residue was treated with water
(150mL).

The resulting pale grey solid was filtered off, washed with water (3 x 100mL),
and
dried in vacuo at 80 C to provide the title compound, 21.26g.

'H NMR (CDCI3, 400MHz) 8: 3.79 (q, 2H), 3.98 (s, 3H), 4.07 (t, 2H), 4.77 (t,
2H),
7.87 (br s, I H), 8.41 (br s, 1 H).
MS ES- m/z 335 [M-H]"
Preparation 213
Methyl 5,7-dioxo-1-[2-(3,3,3-trifluoropropoxy)ethyl]-4,5,6,7-tetrahydro-1 H-
pyrazolo[4,3-dlpyrimidine-3-carboxylate
F O
F O iN
NH
F H3C\0
H O
0


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The title compound was obtained as a pale yellow solid from the compound from
preparation 207 and 1,1'-carbonyldiimidazole, following a similar procedure to
that
described in preparation 212.

'H NMR (CDCI3, 400MHz) 8: 2.26 (m, 2H), 3.61 (t, 2H), 3.88 (t, 2H), 3.98 (s,
3H),
4.75 (t, 2H), 8.05 (s, 1 H), 8.49 (s, 1 H).
MS m/z 351 [MH]+
Preparation 214
Methyl 5,7-dioxo-l-[2-(3-fluoropropoxy)ethyll-4,5,6,7-tetrahYdro-1 H-
pyrazolo[4,3-
dlpy ri m i d i n e-3-ca rb oxy l a te
O


F iN NH H3C\0

H O
O
A solution of the amine from preparation 208 (2.3g, 8.Ommol) in acetonitrile
(35mL)
was added dropwise to a stirred solution of 1,1'-carbonyldiimidazole (2.0g,
12.3mmol) in refluxing acetonitrile (35mL) under nitrogen. The mixture was
then
heated under reflux for 2 hours, and cooled to room temperature. The resulting
solid
was filtered off, washed with acetonitrile and the filtrate evaporated under
reduced
pressure. The residue was triturated with water, the solid filtered off and
the two
isolated solids combined and dried in vacuo to afford the title compound,
2.3g.

'H NMR (DMSO-D6, 400 MHz) 8: 1.70-1.92 (m, 2H), 3.42 (t, 2H), 3.79 (t, 2H),
3.83,(s,
3H), 4.27 (dd, 1 H), 4.40 (dd, 1 H), 4.65 (m, 2H).
MS APCI+ m/z 315 [MH]+
Preparation 215
Methyl 5,7-dichloro-l-[(2S)-2-methoxypropyll-1 H-pyrazolo[4,3-d]pyrimidine-3-
carboxylate


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H3C
CI
H3C_O
N I N
N N
\
CI
H3~
O
O
Phosphorous oxychloride (3.46mL, 37.2mmol) was added to a solution of the
compound from preparation 209 (700mg, 2.48mmol) and tetraethylammonium
chloride hydrate (616mg, 3.72mmol) in acetonitrile (8mL) and the reaction
mixture
heated under reflux for 24 hours. The cooled mixture was concentrated under
reduced pressure and the residue azeotroped with toluene (3x) to provide the
title
compound as a white solid.

'H NMR (CDCI3, 400MHz) S: 1.30 (d, 3H), 3.15 (s, 3H), 3.90 (m, 1 H), 4.10 (s,
3H),
4.68 (dd, 1 H), 4.98 (dd, 1 H).


Preparation 216
Methyl 5,7-dichloro-1-[2-(cyclobutyloxy)ethLrl]-1 H-pyrazolo[4,3-dlpyrimidine-
3-
carboxylate

O
CI
N N
N~ i J
~+ N CI
H3li`
O
O
N,N-Diisopropylethylamine (3.4mL, 19.5mmol) was added dropwise to a solution
of
the compound from preparation 210 (2g, 6.5mmol), phosphorous oxychloride
(9.04mL, 97.3mmol) and tetraethylammonium chloride (2.15g, 13.Ommol) in
acetonitrile (25mL) and the reaction heated under reflux for 18 hours. Tic
analysis
showed starting material remaining, so additional phosphorous oxychloride
(10mL,


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107mmol) was added and the reaction heated under reflux for a further 24
hours.
The cooled mixture was concentrated under reduced pressure and the residue
azeotroped with toluene (2x100mL). The product was dissolved in
dichloromethane
(500mL), washed with water (3x200mL), dried over magnesium sulphate and
evaporated under reduced pressure. The crude product was purified by column
chromatography using an Isolute silica gel cartridge and an elution gradient
of
ethyl acetate:pentane (20:80 to 100:0) to provide the title compound as a
white solid,
1.0g.
'H NMR (CDCI3, 400MHz) S: 1.40 (m, 1 H), 1.55-1.75 (m, 3H), 2.10 (m, 2H), 3.80
(m,
3H), 4.10 (s, 3H), 5.00 (t, 2H).
Preparation 217
Methyl 5,7-dichloro-l-[2-(2,2-difluoroethoxy)ethyll-1 H-pyrazolo[4,3-
dlpyrimidine-3-
carboxylate
CI
F N N I N
F ~
N CI
H3~
O
0
Phosphorous oxychloride (14mL, 148mmol) was added portionwise to a solution of
the compound from preparation 211 (3.13g, 9.84mmol) and tetraethylammonium
chloride (4.08g, 2.46mmol) in propionitrile (50mL) and the reaction then
stirred under
reflux for 18 hours. The cooled mixture was concentrated under reduced
pressure
and the residue azeotroped with toluene (2x). The residual solid was
triturated with
pentane:ether (40mL:10mL), and the resulting solid filtered off. This was pre-
adsorbed onto silica gel and purified by column chromatography on silica gel
using
ethyl acetate:pentane (34:66) to afford the title compound as a white solid,
2.69g.
'H NMR (CDCI3, 400MHz) 8: 3.55 (m, 2H), 4.03 (t, 2H), 4.06 (s, 3H), 5.00 (t,
2H),
5.66 (m, 1 H).
Microanalysis found: C, 37.14; H, 2.85; N, 15.68. C11H1oCI2F2N403 requires C,
37.20;
H, 2.84; N, 15.78%.


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Preparation 218
Methyl 5,7-dichloro-1-L2-(2,2,2-trifluoroethoxy)ethyll-1 H-pyrazoloj4,3-
dlpyrimidine-3-
carboxylate
CI
F~O i
N
F F
N%`CI
~ Hs.
O
O
A mixture of the compound from preparation 212 (10g, 29.8mmol), phosphorous
oxychloride (42mL, 447mmol) and tetraethylammonium chloride hydrate (14.8g,
89.4mmol) in propionitrile (125mL) was stirred under reflux for 8 hours. The
cooled
mixture was concentrated under reduced pressure and the residue azeotroped
with
toluene. The product was partitioned between dichloromethane (600mL) and water
(500mL) and the layers separated. The aqueous solution was further extracted
with
dichloromethane (2x500mL) and the combined organic solutions washed with water
(500mL) and brine (200mL), then dried over magnesium sulphate an'd
concentrated
under reduced pressure. The crude product was purified by column
chromatography
on silica gel using an elution gradient of ethyl acetate:pentane (33:67 to
50:50) to
afford the title compound as a white solid, 5.4g.

'H NMR (CDCI3, 400MHz) 5: 3.75 (q, 2H), 4.10 (s, 3H), 4.15 (t, 2H), 5.05 (t,
2H).
MS APCI+ m/z 373 [M]+
Preparation 219
Methyl 5,7-dichloro-1-[2-(3,3,3-trifluoropropoxy)ethyl]-1 H-pyrazolo f4,3-
dlpyrimidine-
3-carboxylate
F CI

F
O iN
4-1-
F

N HA N CI
O
O
A mixture of the compound from preparation 213 (3.28g, 9.37mmol), phosphorous
oxychloride (13.1 mL, 140mmol) and tetraethylammonium chloride hydrate (3.88g,


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23.4mmol) in propionitrile (50mL) was stirred under reflux for 18 hours. The
cooled
mixture was concentrated under reduced pressure and the residue azeotroped
with
toluene. The product was partitioned between dichloromethane (50mL) and water
(50mL) and the layers separated. The aqueous solution was further extracted
with
dichloromethane (2x5OmL) and the combined organic solutions dried over
magnesium sulphate and concentrated under reduced pressure. The residue was
triturated with pentane:ether, the resulting solid filtered off, washed with
pentane and
dried in vacuo to give the title compound as a solid, 3.2g

'H NMR (CDCI3, 400MHz) 8: 2.20 (m, 2H), 3.57 (t, 2H), 3.90 (t, 2H), 4.06 (s,
3H),
4.99 (t, 2H).
MS+ m/z 387 [MH]+
Preparation 220
Methyl 5,7-dichloro-l-f2-(3-fluoropropoxy)ethyl]-1 H-pyrazolo[4,3-dlpyrimidine-
3-
carboxylate
---iN CI
O
N
F ~
N CI
H3~
O
O
The title compound was obtained as a cream coloured solid in 86% yield, from
the
compound from preparation 214, following a similar procedure to that described
in
preparation 219.
'H NMR (CDCI3,400 MHz) 8: 1.76-86 (m, 2H), 3.48 (t, 2H), 3.95 (t, 2H), 4.09
(s, 3H),
4.29 (dd, 1 H), 4.42 (dd, 1 H), 5.01(t, 2H).
MS APCI+ m/z 351 [MH]+
Preparation 221


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Methyl 5-chloro-l-[(2S)-2-methoxypropyl]-7-[(4-methylpyridin-2-yl)amino]-1 H-
pyrazo I o f 4, 3-cq py ri m i d i n e-3-ca rb oxy l ate
CH3
H3C
HN N
H3C~0
N
o
N~ ( ~ N

H3C\ N CI
O
A solution of 2-amino-4-methylpyridine (850mg, 7.83mmol) in dimethylsulphoxide

(7mL) was warmed to 30 C, and the dichloro compound from preparation 215
(500mg, 1.56mmol) added. The reaction was stirred for a further 2 hours at 30
C
and then cooled to room temperature. The reaction mixture was poured into
water
(100mL) and extracted with dichloromethane (2x200mL). The combined organic
solutions were washed with water (200mL), 1 M citric acid solution (100mL)
then
dried over magnesium sulphate and concentrated under reduced pressure. The
product was triturated with ether, the solid filtered and dried to afford the
title
compound as yellow crystals, 200mg.

'H NMR (DMSO-D6 400MHz) 8: 1.18 (d, 3H), 2.40 (s, 3H), 3.25 (m, 1 H), 3.30 (s,
3H),
3.90 (s, 3H), 4.85 (d, 2H), 7.00 (br s, I H), 8.20 (br s, 1 H).
MS APCI- m/z 389 [MH]"


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Preparation 222
Methyl 7-f f 4-({[tert-butyl(dimethyl)sil ly loxy}methyl)pyridin-2-y11aminol-5-
chloro-1-(2-
ethoxyethyl)-1 H-pyrazolo[4,3-dlpyrimidine-3-carboxylate
H3C
0 O\ ICH3
HN Si CH3
N HaC ~CH3
N N CH3
\ / CI
N
H3~
O
O
A mixture of the dichloro compound from preparation 58 (400mg, 1.25mmol) and 4-

(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (WO 2001 017995, prep
8-5)
(746mg, 3.13mmol) in dichloromethane (10mL) was stirred at room temperature
for
18 hours. The mixture was partitioned between water (30mL) and dichloromethane
(30mL), the layers separated and the organic phase dried over,magnesium
sulphate
and evaporated under reduced pressure. The resulting yellow oil was purified
by
column chromatography on an Isolute silica gel cartridge using an elution
gradient
of ethyl acetate:pentane (0:100 to 70:30) to afford the title compound, 229mg.

'H NMR (MeOD-D6, 400MHz) S: 0.06 (s, 6H), 0.87 (s, 9H), 0.99 (t, 3H), 3.48 (q,
2H),
3.87 (m, 2H), 3.88 (s, 3H), 4.53 (s, 2H), 4.88 (m, 2H), 6.96 (m, 1 H), 8.12
(m, 1 H)
MS ES+ m/z 521 [MH]+
Preparation 223
- Methyl 5-chloro-1-(2-propoxyethrLl)-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-
d]pyrimidine-3-carboxylate

H N
H3C N N
N\ ~
H ~
N CI
sC
O
0


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A mixture of the dichloro compound from preparation 57 (1.33g, 4mmol) and 2-
aminopyridine (1.88g, 20mmol) in dichloromethane (1 6mL) was stirred at 35 C
for
18 hours. The reaction was diluted with dichloromethane (200mL), the mixture
washed with 1 M citric acid solution (2x 50mL), dried over magnesium sulphate
and
evaporated under reduced pressure to afford the title compound as a yellow
solid,
1.48g.
'H NMR (DMSO-D6 + 1 drop TFA-d, 400MHz) b: 0.80 (t, 3H), 1.38 (m, 2H), 3.37
(t,
2H), 3.85 (t, 2H), 3.88 (s, 3H), 4.94 (t, 2H), 7.20 (m, 1 H), 8.01 (m, 1 H),
8.10 (d, 1 H),
8.38 (d, 1 H).
MS APCI+ m/z 391 [MH]+
Preparation 224
Methyl 5-chloro-1-[2-(cyclobutyloxy)eth Ir1-7_[(4-methylpyridin-2-yl)amino]-1
H-
pyrazolo[4,3-dj pyrimidine-3-carboxylate

i
O
HNN~ I
CH3
N N
N~
~+ N CI
H3li`
O
O
A mixture of the dichloro compound from preparation 216 (1.0g, 2.90mmol) and 2-

amino-4-picoline (1.57g, 14.53mmol) in dichloromethane (12mL) were stirred at
room temperature for 18 hours. The mixture was partitioned between
dichloromethane (250mL) and 1 M citric acid solution (100mL) and the layers
separated. The organic layer was washed again with 1 M citric acid solution
(100mL),
water (100mL), and brine (20mL) then dried over magnesium sulphate and
evaporated under reduced pressure. The product was suspended in ether (50mL),
the mixture sonicated, then filtered and the solid dried in vacuo to afford
the title
compound as a yellow solid, 618mg.


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'H NMR (DMSO-D6+TFA-d, 400MHz) 8: 1.35 (m, 1 H), 1.50 (m, I H), 1.70 (m, 2H),
2.00 (m, 2H), 2.42 (s, 3H), 3.75 (t, 2H), 3.90 (m, 4H), 4.95 (t, 2H), 7.10 (d,
1 H), 7.82
(s, 1 H), 8.30 (d, 1 H).
MS APCI+ m/z 417 [MH]+
Preparation 225
Methyl 5-chloro-l-[2-(2,2-difluoroethoxy)ethyll-7-[(4-methyIpyridin-2-
rLI)amino]-1 H-
pyr azolo[4,3-dlpyrimidine-3-carbox I~

~aCH3
HN F O N N ~N

F N~ I ~CI
H3~
O
O
The title compound was prepared as a yellow solid n 56% yield from the chloro
compound from preparation 217 and 2-amino-4-picoline (1.62g, 15mmol) following
the procedure described in preparation 224.

'H NMR (DMSO-D6 + 1 drop TFA-d, 400MHz) 6: 2.40 (s, 3H), 3.68 (m, 2H), 3.88
(s,
3H), 4.00( t, 2H), 5.05 (t, 2H), 6.00 (m, 1 H), 7.04 (d, 1 H), 7.76 (s, 1 H),
8.24 (d, 1 H).
Preparation 226
Methyl 5-chloro-7-[(4-methylpyridin-2-yl)amino]-1-[2-(2,2,2-
trifluoroethoxy)ethyl]-1 H-
pyrazolo[4,3-d]pyrimidine-3-carboxylate
~aCH3
HN F~ i
N
F F _
~
N%~CI
H3C~
O
O
A mixture of the chloro compound from preparation 218 (5.6g, 14.9mmol) and 2-
amino-4-picoline (4.85g, 44.8mmol) in acetonitrile (60mL) was stirred under
reflux for


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hours. The reaction mixture was cooled and diluted with 10% aqueous citric
acid
solution (33.6mL) and the mixture stirred for 10 minutes. The mixture was then
cooled in ice for 30 minutes, the resulting precipitate filtered off, washed
with ice-
cold acetonitrile:water solution (50:50 by volume, 37mL) and ice-cold water
(19mL).
5 The solid was then dried in vacuo to afford the title compound, 5.05g.

'H NMR (DMSO-D6, 400MHz) 8: 2.38 (s, 3H), 3.81 (s, 3H), 4.00 (m, 4H), 5.02 (br
s,
2H), 6.85 (br s, 1 H), 7.64 (br s, 1 H), 8.04 (br s, 1 H).
MS ES+ m/z 445 [MH]+
Preparation 227
Methyl5-chloro-7-[(3-methylphenyl)aminol-1-[2-(2,2,2-trifluoroethoxy)eth I~-1H-

pyrazolo[4,3-dlpyrimidine-3-carbox ly ate

F F
F

0
HN / I
~ CH3
N N
N~
N CI
H3C~
O
O
A mixture of the chloro compound from preparation 218 (746mg, 2mmol) and 3-
methylaniline (650 L, 6mmol) in dimethylsulphoxide (8mL) was stirred at room
temperature for 3 hours. The mixture was partitioned between dichloromethane
(200mL) and water (50mL), and the layers separated. The organic phase was
washed with I M hydrochloric acid (20mL) and water (2x5OmL), then dried over
magnesium sulphate and evaporated under reduced pressure to afford the title
compound as a white solid, 880mg.

'H NMR (CDCI3, 400MHz) 8: 2.38 (s, 3H), 3.98 (q, 2H), 4.05 (s, 3H), 4.30 (t,
2H),
4.90 (t, 2H), 7.00 (d, 1 H), 7.31 (m, 1 H), 7.35 (s, 1 H), 7.55 (d, 1 H), 8.45
(s, 1 H).
MS APCI+ m/z 444 [MH]+
Preparation 228


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M et hyl 5-c h l o ro-7- [(4-fl u o ro-3- m ethyl p h e ny l)a m i n o]-1-[2-
(2 , 2, 2-trifl u o ro eth oxy )et hy l]_
1 H-pyrazolo[4,3-djpyrimidine-3-carboxylate
F
F F CH3
F
O
HN

N
N~
N N
CI
H3C\
O
O
The title compound was obtained from the chloro compound from preparation 218
and 4-fluoro-3-methylamine, following the procedure described in preparation
227.

'H NMR (CDCI3, 400MHz) 8: 2.30 (s, 3H), 3.98 (q, 2H), 4.05 (s, 3H), 4.27 (t,
2H),
4.90 (s, 2H), 7.06 (m, 1 H), 7.38 (m, 1 H), 7.47 (m, 1 H), 8.36 (s, 1 H).
MS APCI+ m/z 462 [MH]+
Preparation 229
Methyl 5-chloro-7-r(4-methylpyridin-2-yl)amino]-1-[2-(3,3,3-
trifluoropropoxy)ethyl]-
1 H-pyrazolof4,3-d]pyrimidine-3-carboxylate

F
F
F N
HN CH3
N N
N~ I ~ -
N CI
H3C~
O
O
The title compound was obtained as a solid in 74% yield from the compound from
preparation 219 and 2-amino-4-picoline, following the procedure described in
preparation 223.


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'H NMR (DMSO-D6+ I drop TFA-d, 400MHz) 8: 2.41 (s, 3H), 2.44 (t, 2H), 3.63 (t,
2H), 3.88 (s, 3H), 3.91(t, 2H), 5.01 (t, 2H), 7.04 (d, 1 H), 7.79 (s, 1 H),
8.21 (d, 1 H).
MS APCI+ m/z 459 [M]+

Preparation 230
Methyl 5-chloro-1-[2-(3-fluoropropoxy)ethZll-7-[(4-methylpyridin-2-yl)aminol-1
H-
pyrazolo[4,3-dlpyrimidine-3-carboxylate
F N
O
HN CH3
N
N~ I N ~ N
H3C~ CI
O
O
The title compound was obtained as a solid in 75% yield from the compound from
preparation 220 and 2-amino-4-picoline, following the procedure described in
preparation 223.

'H NMR (DMSO-D6+ 1 drop TFA-d, 400MHz) S: 1.68-1.82 (m, 2H), 2.40 (s, 3H),
3.49
(t, 2H), 3.85-3.89 (m, 5H), 4.21-4.36 (m, 2H), 4.99 (t, 2H), 7:01 (d, 1 H),
7.81 (s, 1 H),
8.19 (d, 1 H).
MS APCI+ m/z 423 [M]+
Preparation 231
5-Chloro-1-(2-ethoxyethyl)-7-{r4-(hydroxymethyl)pyridin-2-Ll]amino}-1 H-
pyrazolof4,3-
d]pyrimidine-3-carbox li
H3C
N
O OH
HN
N N
N~ ~
N CI
HO
0


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A solution of the compound from preparation 222 (229mg, 0.44mmol) in I N
sodium
hydroxide solution (2.2mL) and dioxan (10mL) was stirred at room temperature
for
72 hours. The mixture was acidified to pH 4 using 1 N hydrochloric acid and
extracted with a solution of 10% methanol in dichloromethane. The combined
organic extracts were dried over magnesium sulphate and evaporated under
reduced pressure to afford the title compound as a yellow solid, 140mg.

'H NMR (DMSO-D6, 400MHz) 5: 1.07 (t, 3H), 3.55 (q, 2H), 3.93 (t, 2H), 4.65 (t,
2H),
4.99 (s, 2H), 5.60 (m, 1 H), 7.10 (m, 1 H), 8.29 (m, 1 H).

Preparation 232
5-Chloro-l-[2-(cyclobutyloxy)ethyll-7-[(4-meth rLlp rid~yl)aminol-1H-
pyrazolo[4,3-
a'lpyrimidine-3-carboxylic acid

N
HN CH3
N N
N~ ~
N CI
HO
O
A solution of the ester from preparation 224 (600mg, 1.44mmol) in dioxane
(5mL)
and 1 N sodium'hydroxide solution (5mL) was stirred at room temperature for 18
hours. The solution was concentrated under reduced pressure and diluted with 1
M
citric acid solution (25mL). The resulting precipitate was filtered off,
washed with
ether and dried in vacuo at 50 C to afford the title compound as a yellow
solid,
566mg.
'H NMR (DMSO-D6+TFA-d, 400MHz) 8: 1.35 (m, 1 H), 1.55 (m, 1 H), 1.75 (t, 2H),
2.05
(m, 2H), 2.40 (s, 3H), 3.79 (t, 2H), 3.95 (m, 1 H), 4.90 (t, 2H), 6.98 (d, 1
H), 7.85 (s,

1 H), 8.20 (d, 1 H).
MS APCI+ m/z 403 [MH]+
Preparation 233


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5-Chloro-7-[(4-methylpyridin-2-yl)aminol-112-(2,2,2-trifluoroethoxy)ethyll-1 H-

p rarzolo[4,3-dlpyrimidine-3-carboxylic acid
F F
F

0 I
N
HN \ CH3

N N
N~ ~
N CI
HO
O
A mixture of the ester from preparation 226 (1.2g, 2.70mmol) and 1 M sodium
hydroxide solution (4.1 mL, 4.1 mmol) in dioxane (17.4mL) was stirred at room
temperature for 18 hours. The reaction mixture was concentrated under reduced
pressure and the residue dissolved in water (50mL). The solution was washed
with
dichloromethane (10mL), and then acidified using,1 M citric acid. The
resulting solid
was filtered off and dried in vacuo to afford the title compound, 925mg.

'H NMR (DMSO-D6, 400MHz) 6: 2.50 (s, 3H), 3.32 (q, 2H), 4.07 (t, 2H), 5.06 (t,
2H),
6.93 (d, 1 H), 7.73 (s, 1 H), 8.13 (d, 1 H).

Preparation 234
3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1-(2-ethoxyethyl)-N-(6-
methLrlpyrimidin-4-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine N

0 CH3 N^I
HN"' CH
3
N N

H3C CH3 N CI
H3C~--Si" H3C CH 0

3


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A solution of 4-amino-6-methylpyrimidine (1.13g, 10.4mmol) and sodium
bis(trimethylsilyl)amide (3.80g, 20.74mmol) in tetrahydrofuran (40mL) was
stirred at
room temperature for 15 minutes. A solution of the dichloro compound from
preparation 154 (3.5g, 8.64mmol) in tetrahydrofuran (50mL) was added and the
reaction stirred at room temperature for 1.5 hours. The reaction mixture was
concentrated under reduced pressure and the residue partitioned between
dichloromethane and saturated ammonium chloride solution and the layers
separated. The organic phase was dried over magnesium sulphate and evaporated
under reduced pressure to give a red solid. The product was purified by column
chromatography using an Isolute silica gel cartridge and an elution gradient
of
methanol:dichloromethane (0:100 to 3:97) to provide the title compound as an
orange solid, 3.7g.

'H NMR (DMSO-D6, 400MHz) 8: 0.02 (s, 6H), 0.79 (s, 9H), 1.06 (t, 3H), 2.44 (s,
3H),
3.53 (q, 2H), 3.82 (t, 2H), 4.71 (t, 2H), 4.89 (s, 2H), 8.19 (s, 1 H), 8.59
(s, 1 H).
MS ES+ m/z 478 [MH]+
Preparation 235
{5-Chloro-l-(2-ethoxyethyl)-7-[(6-methylpyrimidin-4-yl)amino]-1 H-pyrazolo[4,3-

d]pyrimidin-3- rl methanol

0 CH3 NI
HN"' CH
3
N N
N~
N CI
HO

A mixture of the compound from preparation 234 (3.7g, 7.75mmol) and
tetrabutylammonium fluoride (23.2mL, 1 M in tetrahydrofuran, 23.2mmol) in
tetrahydrofuran (61 mL) was stirred at room temperature for 18 hours. The
mixture
was concentrated under reduced pressure and the residue partitioned between
ethyl
acetate (100mL) and water (100mL) and the layers separated. The aqueous
solution
was extracted with further ethyl acetate (2x5OmL) and the combined organic
solutions were concentrated under reduced pressure.


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The residue was purified by column chromatography using an Isolute silica gel
cartridge and an elution gradient of methanol:dichloromethane (0:100 to 2:98)
to
provide the title compound, 2.6g.

'H NMR (CD3OD, 400MHz) 8: 1.19 (t, 3H), 2.57 (s, 3H), 3.66 (q, 2H), 3.96 (t,
2H),
4.84 (t, 2H), 4.90 (s, 2H), 8.33 (s, 1 H), 8.72 (s, 1 H).
MS ES+ m/z 364 [MH]+
Preparation 236
5-Chloro-1-(2-ethoxyethyl)-7-[(6-methylpyrimidin-4-yl)amino]-1 H-pyrazolo[4,3-
dlpyrimidine-3-carbaldehyde

O/"--CH3 N^i
HN"' ~CH
3
N~
N H N
N C~
O
Dess-Martin periodinane (4.56g, 10.73mmol) was added portionwise to an ice-
cooled solution of the alcohol from preparation 235 (2.6g, 7.15mmol) in
dichloromethane (150mL) and the reaction then stirred at room temperature for
a
further 2 hours. A solution of sodium thiosulphate (7.5g, 30mmol) in water
(75mL)
was added dropwise, followed by saturated sodium bicarbonate solution (75mL)
and then ether (75mL). The mixture was stirred for 15 minutes, and the layers
separated. The aqueous solution was extracted with further dichloromethane
(2x4OmL) and the combined organic solutions dried over magnesium sulphate and
evaporated under reduced pressure. The residual brown solid was purified by
column chromatography using an Isolute0 silica gel cartridge and an elution
gradient of ethyl acetate:pentane (0:100 to 100:0) to provide the title
compound as a
solid, 1.66g.

'H NMR (CDCI3, 400MHz) 8: 1.25 (t, 3H), 2.63 (s, 3H), 3.72 (q, 2H), 4.06 (t,
2H), 4.91
(t, 2H), 8.29 (s, 1 H), 8.81 (s, 1 H), 10.34 (s, 1 H), 10.42 (s, 1 H).
MS ES+ m/z 362 [MH]+


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Preparation 237
5-Chloro-l-(2-ethoxyeth rl -7-[(6-methylpyrimidin-4-yl)amino]-1 H-pyrazoloL,3-
d]pyrimidine-3-carboxylic acid N

O/~-CH3 N^I
HNCH 3
N N
N~
N CI
O OH

2-Methyl-2-butene (160mL, 0.32mo1) was added to a solution of the aldehyde
from
preparation 236 (1.66g, 4.59mmol) in t-butanol (300mL). A solution of sodium
chlorite (4.96g, 55.1 mmol) and sodium dihydrogen phosphate (5.07g, 42.2mmol)
in
water (60mL) was added dropwise over 5 minutes, and the reaction then stirred
at
room temperature for 1 hour. The reaction mixture was diluted with
dichloromethane
(300mL) and water (150mL) and the layers separated. The aqueous layer was
allowed to evaporate and the resulting precipitate was filtered off and dried
in vacuo
to give the title compound, 1.02g.

'H NMR (400 MHz, DMSO-D6) 8: 1.07 (t, 3H), 2.48 (s, 3H), 3.51 (m, 2H), 3.88
(t, 2H),
4.90 (t, 2H), 8.02 (br s, 1 H), 8.78 (s, 1 H).
MS APCI+ m/z 378 [MH]+
Preparation 238
5-Chloro-1-(2-ethoxyethyl)-7-[(3-methylphenyl)amino]-1 H-indazole-3-carboxylic
acid
O CH
. ' \ I
HN CH3
i

CI
O
OH


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A mixture of the ester from preparation 81 (800mg, 2.06mmol) and I N sodium
hydroxide solution (5mL, 5mmol) in dioxan (3mL) was stirred at room
temperature
for 18 hours. The reaction was concentrated under reduced pressure and the
residue diluted with 1 M citric acid solution and the mixture sonicated. The
resulting
precipitate was filtered off, washed with water and ether and dried in vacuo
to give
the title compound as a white solid, 600mg.

'H NMR (DMSO-D6, 400MHz) 8: 1.00 (t, 3H), 2.35 (s, 3H), 3.50 (q, 2H), 3.82 (t,
2H),
4.95 (t, 2H), 7.01 (d, 1 H), 7.35 (t, 1 H), 7.41 (s, 1 H), 7.50 (d, 1 H), 9.39
(s, 1 H).
MS APCI+ m/z 376 [MH]+
Preparation 239
5-Chloro-1-(2-ethoxyethyl)-7-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yi)aminol-1
H-
indazole-3-carboxylic acid

O
~ CH3 CfN"'CH3
HN N
N I
CI
O
OH
The compound from preparation 58 (10.85g, 34mmol) was added portionwise to a
solution of 3-amino-1-methyl-1,6-dihydropyridin-6-one (EP 677519) (4.6g,
37mmol)
and N-ethyldiisopropylamine (5.92mL, 34mmol) in dimethylsulphoxide (40mL), and
the reaction then stirred at room temperature for 4 hours. The mixture was
diluted
with water (600mL), and the resulting solid filtered off, washed with water
and dried
in vacuo, 10.8g.
A portion of this solid (6.75g, 16.59mmol) was dissolved in dioxan (65mL) and
the
solution treated with 1 N sodium hydroxide (33mL, 1 M, 33mmol), and the
reaction
stirred at room temperature for 18 hours. The reaction was concentrated under
reduced pressure, the residue dissolved in water (120mL), washed with
dichloromethane (15mL), then acidified to pH 3 using solid citric acid. The
resulting


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precipitate was filtered off, washed with water (3x2OmL) and dried in vacuo to
afford
the title compound as a yellow solid, 6.19g.

'H NMR (DMSO-D6, 400MHz) 8: 0.95 (t, 3H), 3.40 (q, 2H), 3.47 (s, 3H), 3.79 (t,
2H),
.4.92 (t, 2H), 6.49 (d, 1 H), 7.58 (dd, 1 H), 7.90 (s, 1 H),
MS APCI+ m/z 376 [MH]+
Preparation 240
Benzyl cyclobutylcarbamate

N

O
Benzyl chloroformate (5.2mL, 36.4mmol) was added dropwise to an ice-cold
solution
of cyclobutylamine (2g, 28.1 mmol) in dichloromethane (20mL), with stirring.
Triethylamine (4.7mL, 33.7mmol) was added dropwise to the ice-cold solution,
and
once the addition was complete the reaction was allowed to warm to room
temperature and stirred for 18 hours. The reaction was washed with saturated
sodium bicarbonate solution (x2), dried over sodium sulphate and concentrated
under reduced pressure. The residue was purified by column chromatography on
silica gel using dichloromethane as eluant to afford the title compound,
3.72g.

'H NMR (CDCI3, 300MHz) 6: 1.68 (m, 2H), 1.82 (m, 2H), 2.35 (m, 2H), 4.19 (m, 1
H),
4.92 (m, 1 H), 5.14 (s, 2H), 7.2-5-7.39 (m, 5H).
MS TSP+ m/z 223.2 [MH]+
Preparation 241
N-Cyclobutyl-N-methylamine hydrochloride
HCI H
N, CH3

A solution of the compound from preparation 240 (500mg, 2.43mmol) was added
dropwise to an ice-cold solution of lithium aluminium hydride (12.18mL, 1 M in
tetrahydrofuran, 12.18mmol) in tetrahydrofuran (12mL), and the reaction
mixture


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stirred at room temperature for 24 hours. The mixture was cooled to 0 C, water
(0.46mL), followed by 15% sodium hydroxide solution (0.46mL) and finally
further
water (1.4mL) were added dropwise. The resulting precipitate was filtered off
and
washed with ether. The filtrate was washed with water and acidified to pH 2
using
1 M hydrochloric acid in ether. The solution was allowed to evaporate at room
temperature, the residual oil dissolved in methanolic ether, dried over sodium
sulphate and evaporated under reduced pressure to provide the title compound.

'H NMR (CDCI3, 400MHz) S: 1.78-2.04 (m, 2H), 2.34 (m, 2H), 2.44 (m, 2H), 2.54
(s,
3H), 3.58 (m, I H), 9.60 (br s, 2H).

Preparations 242 to 244
CH3
0
HN N
O
N N
N~ I 'I
~N, R3
N I
O R4
O
H3C
The appropriate amine (HNR3R4) (2mmol) and cesium fluoride (1 00mg, 0.67mmol)
were added to a solution of the chloride from preparation 233 (260mg,
0.67mmol) in
dimethylsulphoxide (2mL) in a Reactivial . The reaction mixture was then
sealed

and-heated at 120 C for 18 hours. The cooled solution was partitioned between
dichloromethane (50mL) and water (50mL) and the layers separated. The organic
phase was washed with water (50mL), dried over magnesium sulphate and
evaporated under reduced pressure. The crude products were purified by column
chromatography on silica gel using dichloromethane:methanol (98:2) as eluant
to
afford the title compounds.

Prep -NR3R4 Data
No


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242 CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 0.65 (t, 3H),
1.15 (t, 3H), 1.38 (m, 2H), 3.20 (s, 3H), 3.33 (t, 2H),
~N\CH3 3.64 (q, 2H), 3.84 (t, 2H), 3.90 (s, 3H), 4.98 (t, 2H),
7.28 (m, 1 H), 8.18 (m, 2H), 8.36 (d, 1 H).
MS APCI+ m/z 414 [MH]+

243 CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) b: 0.65 (t, 3H),
~N~CH3 1.17 (t, 6H), 1.35 (m, 2H), 3.28 (t, 2H), 3.64 (m, 4H),
3.84 (t, 2H), 3.87 (s, 3H), 4.96 (t, 2H), 7.27 (m, I H),
8.17 (m, 2H), 8.35 (m, 1 H).
MS APCI+ m/z 428 [MH]+

244 CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 0.65 (t, 3H),
A,"N-,~,rCH3 1.18 (d, 6H), 1.36 (m, 2H), 3.05 (s, 3H), 3.30 (t, 2H),
CH3 3.82 (t, 2H), 3.90 (s, 3H), 4.72 (m, 1 H), 4.95 (t, 2H),
7.29 (m, 1 H), 8.18 (m, 2H), 8.36 (d, 1 H).
MS APCI+ m/z 428 [MH]+
Preparations 245 to 249
CH3
F R7c
O/--(-F
F HN
N N
N \ I / , Rs
N// N
0 O R4
1
H3C
The appropriate amine (HNR3R4) (2mmol) was added to a solution of the chloride
from preparations 227 or 228 (296mg, 0.67mmol) and cesium fluoride (101 mg,

0.67mmol) in dimethylsulphoxide (2.5mL) in a Reactivial . The reaction mixture
was
then sealed and heated to 120 C for 12 hours. The cooled solution was
partitioned
between dichloromethane (200mL) and water (50mL) and the layers separated. The


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organic phase was washed with water (2x5OmL), dried over magnesium sulphate
and evaporated under reduced pressure, to afford the title compound.

Prep -NR3R4 R' Yield/Data
No
245 /CH3 H 96% yellow gum.

'H NMR (CD3OD, 400MHz) S: 1.17 (t, 3H),
~N\CH3 2.37 (s, 3H), 3.16 (s, 3H), 3.66 (q, 2H), 3.94
(s, 3H), 4.05 (q, 2H), 4.18 (t, 2H), 4.87 (t,
2H), 6.93 (d, 1 H), 7.24 (dd, 1 H), 7.43 (d,
1 H), 7.55 (s, 1 H).
MS APCI+ m/z 467 [MH]+
246 CH3 F Quantitative, Yellow gum

0,,-'NCH3 'H NMR (CD3OD, 400MHz) 8: 1.12 (t, 3H),
2.27 (s, 3H), 3.14 (s, 3H), 3.66 (q, 2H), 3.96
(s, 3H), 4.04 (q, 2H), 4.18 (t, 2H), 4.87 (t,
2H), 7.04 (t, 1 H), 7.42 (m, 1 H), 7.58 (m,
1 H).
MS APCI+ 485 [MH]+
247 CH3 H 96% yellow gum

N"r CH3 'H NMR (CD3OD, 400MHz) 8: 1.20 (d, 6H),
CH3 2.34 (s, 3H), 3.05 (s, 3H), 3.95 (s, 3H), 4.09
(q, 2H), 4.18 (t, 2H), 4.87 (t, 2H), 5.10 (m,
1 H), 6.95 (d, 1 H), 7.24 (dd, 1 H), 7.40 (d,
1 H), 7.55 (s, 1 H).
MS APCI+ m/z 481 [MH]+
248 CH3 F 96% as a yellow gum

~ 'H NMR (CD3OD, 400MHz) 8: 1.08 (t, 6H),
~N~CH3
2.28 (s, 3H), 3.66 (q, 4H), 3.96 (s, 3H), 4.04
(q, 2H), 4.15 (t, 2H), 4.86 (t; 2H), 7.01 (m,
1 H), 7.38 (m, 1 H), 7.58 (s, 1 H).
MS APCI+ m/z 499 [MH]+


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249 CH3 F 93% as a yellow gum

A,--Ny CH3 'H NMR (CD3OD, 400MHz) 8: 1.18 (d, 6H),
CH3 2.26 (s, 3H), 3.02 (s, 3H), 3.95 (s, 3H), 4.02
(q, 2H), 4.16 (t, 2H), 4.87 (t, 2H), 5.04 (m,
1 H), 7.02 (t, 1 H), 7.40 (m, 1 H), 7.55 (m,
1 H).
MS APCI+ m/z 499 [MH]+
Preparations 250 to 258
The compounds of the general formulae shown in the table below were prepared
using the method described for preparations 245 to 249, from the compound from
preparations 225, 229 and 230 and the appropriate HNR3R4 amines.
CH3
F

F ~
HN N
N N
N~ I ~ , R
N
R4
O
O
H3C

Prep -NR3R4 Data
No -
250 /CH3 'H NMR (CD3OD, 400MHz) 8: 1.27 (t, 3H), 2.38 (s,
r 3H), 3.20 (s, 3H), 3.74 (m, 4H), 3.95 (s, 3H), 4.10 (t,
~N\CH3 2H), 4.80 (m, 2H), 6.00 (m, 1 H), 6.98 (m, 1 H), 8.18
(m, 1 H), 8.25 (m, 1 H).
MS APCI+ m/z 450 [MH]+

251 CH3 'H NMR (CD3OD, 400MHz) 8: 1.25 (t, 6H), 2.40 .(s,
A'--NCH3 3H), 3.75 (m, 6H), 3.95 (s, 3H), 4.10 (t, 2H), 4.82 (m,
2H), 6.00 (m, 1 H), 6.95 (m, 1 H), 8.18 (m, 1 H), 8.30


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(m, 1 H).
MS APCI+ m/z 464 [MH]+

252 CH3 'H NMR (CD3OD, 400MHz) 6: 1.24 (d, 6H), 2.40 (s,
A-11"Ny CH3 3H), 3.06 (s, 3H), 3.60 (m, 2H), 3.95 (s, 3H), 4.08 (t,
CH3 2H), 4.80 (m, 2H), 5.10 (m, 1 H), 6.00 (m, 1 H), 6.95
(m, 1 H), 8.18 (m, 1 H), 8.20 (m, 1 H).
MS APCI+ m/z 464 [MH]+
i
F
O N ~
HN ~ CH
F 3

N N
N~ ~Rs
NN
O O Ra
H3C

253 CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) b: 1.12 (t, 3H),
2.46 (s, 3H), 2.37-2.50 (m, 2H), 3.20 (s, 3H), 3.60 (t,
CH3 2H), 3.65 (m, 2H), 3.89-3.91 (m, 5H), 5.00 (t, 2H),
7.19 (d, 1 H), 8.10 (s, 1 H), 8.25 (d, 1 H).
MS APCI+ m/z 482 [MH]+

254 ~,,CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) S: 1.20 (d, 6H),
2.45 (s, 3H), 2.37-2.50 (m, 2H), 3.04 (s, 3H), 3.60 (t,
H3C CH3 2H), 3.89-3.91 (m, 5H), 4.70-4.78 (m, 1 H), 4.99 (t,

2H), 7.18 (d, 1 H), 8.08 (s, 1 H), 8.25 (d, 1 H).
MS APCI+ m/z 496 [MH]+

255 *'~'N^CH 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 1.21 (t, 6H),
3
2.35-2.50 (m, 5H), 3.60 (t, 2H), 3.65 (q, 4H), 3.90 (s,
CH3 3H), 4.99 (t, 2H), 7.19 (d, 1 H), 8.10 (s, 1 H), 8.25 (d,
1 H).
MS APCI+ m/z 496 [MH]+


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~
F
HNNI
\ CH3
N N
N~ ~ ~Rs
N%\N
O Ra
O
H3C
256 ICH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 1.12 (t, 3H),
1.67-1.80 (m, 2H), 2.40 (s, 3H), 3.20 (s, 3H), 3.45 (t,
CH3 2H), 3.65 (q, 2H), 3.87 (t, 2H), 3.90 (s, 3H), 4.23-
4.38 (m, 2H), 4.98 (t, 2H), 7.18 (d, 1 H), 8.10 (s, 1 H),
8.25 (d, 1 H).
MS APCI+ m/z 446 [MH]+

257 'w,~,,CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) b: 1.20 (d, 6H),
1.69-1.78 (m, 2H), 2.45 (s, 3H), 3.00 (s, 3H), 3.45 (t,
H3C CH3 2H), 3.86 (t, 2H), 3.90 (s, 3H), 4.23-4.38 (m, 2H),

4.98 (t, 2H), 4.69-4.76 (m, 1 H), 7.18 (d, 1 H), 8.08 (s,
1 H), 8.24 (d, I H).
MS APCI+ m/z 460 [MH]+

258 *~'N"'~CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 6: 1.20 (t, 6H),
1.68-1.80 (m, 2H), 2.45 (s, 3H), 3.45 (t, 2H), 3.65 (q,
CH3 4H), 3.87 (t, 2H), 3.90 (s, 3H), 4.24-4.39 (m, 2H),

4.97 (t, 2H), 7.18 (d, 1 H), 8.04 (s, 1 H), 8.25 (d, 1 H).
MS APCI+ m/z 460 [MH]+

Preparation 259
Methyl 1-(2-ethoxyethyl)-7-[(4-methylp ridr~ in-2-yl)aminol-5-pyrrolidin-1- I-
r1 H-
pyrazolo[4,3-d]pyrimidine-3-carbox, I~


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CH3
O/_CH3
HN N
N N
N~
N
O O

H3C
The title compound was obtained as a yellow oil, from the chloride from
preparation
72 and pyrrolidine, following a similar procedure to that described in
preparation
245-249, except 5 eq N-ethyldiisopropylamine was added to, the reaction, and
the

product was purified by column chromatography using an Isolute silica gel
cartridge and dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) as
eluant.

'H NMR (CD3OD, 400MHz) 8: 1.05 (t, 3H), 2.02 (m, 4H), 2.40 (s, 3H), 3.60 (q,
2H),
3.65 (m, 4H), 3.90 (m, 5H), 4.80 (t, 2H), 6.95 (d, 1 H), 8.18 (d, 1 H), 8.50
(s, 1 H).
MS APCI+ m/z 426 [MH]+

Preparation 260
Methyl 5-[isopropyl(methyl)amino]-1-[(2S)-2-methoxypropLll-7-[(4-methylpyrid
in-2-
yl)aminol-1 H-p razolo[4,3-dlpyrimidine-3-carbox, I~
CH3
H3C
HN N
H3C_O
iN N
I II
,CH3
N

0 0 ~-CH3
~ H3C
H3C

A mixture of the chloride from preparation 221 (110mg, 0.28mmol), N-
ethyldiisopropylamine (0.25mL, 1.40mmol), N-methylisopropylamine (0.15mL,


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1.40mmol) and tetraethylammonium fluoride (37mg, 0.28mmol) in 1-methyl-2-
pyrrolidinone (1 mL) was heated in a Reactivial at 120 C for 18 hours. The
cooled
mixture was concentrated under reduced pressure and the residue partitioned
between dichloromethane (50mL) and water (50mL) and the layers separated. The
aqueous phase was extracted with additional dichloromethane (50mL), and the
combined organic solutions washed with water (100mL) dried over magnesium
sulphate and evaporated under reduced pressure. The crude product was purified
by column chromatography using an Isolute silica gel cartridge using
dichloromethane as eluant to provide the title compound as a yellow oil, 43mg.

'H NMR (CD3OD, 400MHz) 8: 1.21 (m, 6H), 1.28 (d, 3H), 2.39 (s, 3H), 3.03 (s,
3H),
3.40 (s, 3H), 3.98 (m, 4H), 4.50-4.70 (m, 2H), 5.17 (m, 1 H), 6.92 (d, 1 H),
8.18 (m,
2H).
MS APCI+ m/z 428 [MH]+
Preparation 261
5-Chloro-7-[(4-methyl pyridin-2-yl)aminol-N-(methylsulfon rLl)-1-[2-(2,2,2-
trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxamide
CF3 CH3

O
HN N
iN N N CI

O , NH
O=S~~O
CH3
A mixture of the acid from preparation 233 (300mg, 0.70mmol),
methanesulphonamide (87mg, 0:91mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (175mg, 0.91 mmol) and 4-dimethylamino
pyridine
(102mg, 0.91 mmol) in N,N-dimethylformamide (3mL) was stirred at room
temperature for 18 hours. TIc analysis showed starting material remaining, so


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additional methanesulphonamide (43mg, 0.45mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (87mg, 0.45mmol) and 4-dimethylamino pyridine
(51 mg, 0.45mmol) were added and the mixture stirred for a further 4 hours.
The
mixture was partitioned between dichloromethane (50mL) and water (50mL) and
the
layers separated. The organic solution was washed with 1 N hydrochloric acid
(5mL)
and water (3x50mL) then dried over sodium sulphate and evaporated under
reduced
pressure, to give the title compound, 100mg.

'H NMR (CD3OD, 400MHz) 8: 2.42 (s, 3H), 3.39 (s, 3H), 4.02 (q, 2H), 4.17 (t,
2H),
5.07 (t, 2H), 6.99 (d, 1 H), 7.81 (s, 1 H), 8.18 (d, 1 H).
MS ES- m/z 506 [M-H]-

Example 1
Methyl 1-(2-eth oxyethyl )-5-(N-is o pro pyl-N-m ethyl a m i no )-7-(4-m ethyl
pyrid i n-2-
ylamino)-1 H-pyrazolo[4,3-dlpyrimidine-3-carbox I~ate

H3C~0 N
N
N 3
N~ ~ / "I CH
CH3
H C O N N
3 O CH3
H3C
The chloro compound of preparation 72 (130mg, 0.33mmol) was dissolved in
dimethyl sulphoxide (1 mL) and the solution treated with tetraethylammonium
fluoride
(50mg, 0.33mmol) and N-methylisopropylamine (104 L, 1.Ommol). The reaction
mixture was stirred in a ReactiVialT"^ at 120 C for 18 hours before being
allowed to
cool and concentrated in vacuo. The residue was partitioned between ethyl
acetate
(50mL) and water (50mL) and the organic phase dried over magnesium sulphate
and concentrated in vacuo. The residue was purified by column chromatography
on
silica gel eluting with dichloromethane:methanol 100:0 to 97:3 to yield the
title
product.


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'H NMR (CDCI3, 400MHz) 8: 1.18 (t, 3H), 1.24 (s, 6H), 2.40 (m, 3H), 3.11 (s,
3H),
3.60 (q, 2H), 3.96 (t, 2H), 4.02 (s, 3H), 4.80 (t, 2H), 5.10 (m, 1 H), 6.91
(d, 1 H), 8.18
(m, 1 H), 8.37 (d, 1 H). MS APCI+ m/z 428 [MH]+

Example 2
Methyl 1-(2-ethoxyethLl)-5-(N-ethyl-N-methylamino)-7-(4-meth rLpl yridin-2-
la~ mino)-
1 H-pyr azolo[4,3-dlpyrimidine-3-carboxylate

N-
H3CC N \ /
N\N I\ N CH3

O N~
H3C 0 H C ~CH3
3

The chloro compound of preparation 72 (130mg, 0.33mmol) was dissolved in
dimethyl sulphoxide (1 mL) and the solution treated with tetraethylammonium
fluoride
~
(50mg, 0.33mmol) and N-methylethylamine (86 L, 1.0mmol). The reaction mixture
was heated to 110 C in a ReactiVialTM for 18 hours and then allowed to cool to
room
temperature. The reaction mixture was partitioned between dichloromethane
(50mL)
and water (50mL) and the organic phase washed with water (2x3OmL), dried over
magnesium sulphate and concentrated in vacuo. The residue was purified by
column chromatography on silica gel eluting with dichloromethane:methanol
100:0 to
90:10 to yield the title product.

'H NMR (CD36D, 400MHz) 8: 1.10 (t, 3H), 1.25 (m, 3H), 2.40 (s, 3H), 3.25 (s,
3H),
3.60 (q, 2H), 3.78 (q, 2H), 3.86 (m, 5H), 4.80 (t, 2H), 6.93 (d, 1 H), 8.15
(d, 1 H), 8.32
(s, 1 H). MS APCI+ m/z 414 [MH]+

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for example 2 using the appropriate HNR3R4
amine.


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H3C0~ N

N / ' N CH3
O N-~ N_R3
H3C O 4
No. NR3R4 Data

'H NMR (CD3OD, 400MHz) 8: 1.13 (t, 3H), 1.18 (d,
N CH3 3H), 2.40 (s, 3H), 2.64 (m, 1 H), 2.84 (m, 2H), 3.03
3 (m, 2H), 3.42 (q, 2H), 3.94 (m, 5H), 4.64 (m, 2H),
~NH
4.80 (t, 2H), 6.94 (d, 1 H), 8.18 (m, 2H). MS APCI+
m/z 455 [MH]+

'H NMR (CD3OD, 400MHz) S: 1.08 (t, 3H), 1.84 (d,
1 H), 1.96 (d, 1 H), 2.40 (s, 3H), 3.08 (m, 2H), 3.60 (m,
3.73 (m, 1 H), 3.85 (m, 1 H), 3.92 (m, 5H), 4.82
4 (J.JH 3H),
(m, 2H), 4.97 (m, 1 H), 6.95 (d, 1 H), 8.16 (d, 1 H), 8.30
(m, 1 H). MS APCI+ m/z 453 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.10 (t, 3H), 2.38 (s,
3H), 3.24 (s, 6H), 3.40 (q, 2H), 3.83 (m, 5H), 4.77 (m,
-N(CH3)2 2H), 6.93 (d, 1 H), 8.15 (d, 1 H), 8.34 (s, 1 H). MS

APCI+ m/z 400 [MH]+

= Example 4 was prepared using tert-butyl (1 S,4S)-2,5-diaza-
bicyclo[2.2.1]heptane-2-carboxylate (Aldrich Chem.) as the HNR3R4 amine.
Prior to being purified by column chromatography, the crude product was
5 dissolved in dichloromethane (5mL) and the solution treated with
trifluoroacetic acid (5mL) at room temperature for 4 hours. The reaction
mixture was concentrated in vacuo and the residue partitioned between
dichloromethane (50mL) and saturated sodium hydrogencarbonate solution
(50mL). The organic phase was separated, dried over magnesium sulphate
and concentrated in vacuo.


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Example 6
Methyl 1-(2-ethoxyeth rl -5-(N-isopropyl-N-meth lamino)-7-(6-methylpyridin-2-
lamino)-1 H-pyrazolof4,3-cdlpyrimidine-3-carboxylate
H3C0"~ N
,N N
N / N CH3
~ CH3
HC O N N
3 O CH3
H3C
The chloro compound of preparation 93 (200mg, 0.51 mmol) was added to a
solution

of N-ethyldiisopropylamine (440 1, 2.55mmol), isopropylmethylamine (260 L,
2.55mmol) and caesium fluoride (77mg, 0.51 mmol) in dimethyl sulphoxide (1 mL)
and the reaction mixture heated to 120 C in a ReactiVialTM for 18 hours. The
reaction mixture was concentrated in vacuo and the residue taken up in 1 M
citric
acid solution (5mL) and extracted with dichloromethane (3x25mL). The organics
were combined, dried over magnesium sulphate and concentrated in vacuo to
yield
the title product.

'H NMR (CDCI3, 400MHz) 8: 1.16 (t, 3H), 1.24 (d, 6H), 2.37 (s, 3H), 3.11 (s,
3H),
3.62 (q, 2H), 3.98 (t, 2H), 4.01 (s, 3H), 4.77 (m, 2H), 5.15 (m, 1 H), 6.82
(d, 1 H), 8.18
(d, 1 H), 8.26 (s, 1 H), 9.76 (s, 1 H).
Example 7
Ethyl 1-(2-ethoxyethyl)-5-(N-ethyl-N-meth lamino)-7-(4-methylpyridin-2-
ylamino)-1 H-
pyrazolo(4,3-d]pyrimidine-3-carboxylate
H3C0 N
N
N ~ N CH3
O N~
H3C-/ 0 N~CH
H3C 3


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Th.e ethyl ester of preparation 175 (100mg, 0.25mmol) was dissolved in
dimethyl
sulphoxide (1 mL) and the solution treated with N-methyl-ethylamine (78 L,
0.75mmol) and tetraethylammonium fluoride (37mg, 0.25mmol). The reaction
mixture was then heated to 120 C in a ReactiVialTM for 18 hours before being

allowed to cool. The reaction mixture was concentrated in vacuo, the residue
partitioned between ethyl acetate (50mL) and water (50mL) and the organic
phase
dried over magnesium sulphate and concentrated in vacuo. The residue was
purified
by column chromatography on silica gel eluting with
dichloromethane:acetonitrile
100:0 to 90:10. The crude product was partitioned between dichloromethane
(30mL)
and saturated sodium hydrogencarbonate solution (10mL). The organic phase was
separated, dried over magnesium sulphate and concentrated in vacuo. The
residue
was purified by column chromatography on silica gel eluting with
dichloromethane:methanol:0.88 ammonia 95:5:0.5 to yield the title product.

'H NMR (CDCI3, 400MHz) 8: 1.14 (t, 3H), 1.24 (t, 3H), 1.46 (t, 3H), 2.39 (s,
3H), 3.25
(s, 3H), 3.62 (q, 2H), 3.80 (q, 2H), 3.95 (t, 2H), 4.52 (q, 2H), 4.78 (t, 2H),
6.82 (d,
1 H), 8.20 (d, 1 H), 8.30 (s, 1 H), 9.75 (m, 1 H). MS APCI+ m/z 428 [MH]}

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for example 7 using the appropriate HNR3R4
amine.
H3CO N

N~ / ~ N CH3
H3C--/ O N- N-R3

R
No. NR3R4 Data

8 N,^,,,rCH3 'H NMR (CDCI3, 400MHz) 6: 1.12 (t, 3H), 1.14 (d,
NH 3H), 1.42 (t, 3H), 2.40 (s, 3H), 2.66 (m, 1 H), 2.84
(m, 2H), 3.04 (m, 2H), 3.62 (q, 2H), 3.94 (t, 2H),
4.43 (q, 2H), 4.64 (m, 2H), 4.80 (t, 2H), 6.96 (d,


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1 H), 8.14 (m, 2H). MS APCI+ m/z 469 [MH]+

9 CH3 'H NMR (CDCI3, 400MHz) 8: 1.05 (t, 3H), 1.30 (m,
NCH3 6H), 1.48 (t, 3H), 2.44 (s, 3H), 3.08 (s, 3H), 3.55
CH3 (q, 2H), 3.94 (t, 2H), 4.50 (q, 2H), 4.95 (m, 3H),
6.96 (d, 1 H), 8.12 (s, 1 H), 8.33 (d, 1 H). MS
APCI+ m/z 442 [MH]+

= Example 9 - This compound was isolated without purification by column
chromatography

Example 10
2-(Dimethylamino)ethyl 5-d imethylamino-l-(2-ethoxyethyl)-7-(4-methyl pyridin-
2-
ylamino)-1 H-pyrazolo(4,3-d]pyrimidine-3-carboxylate

H3C0 N \

N / \ N CH3
N -CH
O N 3
H3C-N H C
3
CH3

The title compound was prepared by a method similar to that described for
example
7, using the ester of preparation 176 and a 2M solution of dimethylamine in
methanol.

'H NMR (CD3OD, 400MHz) 8: 1.10 (t, 3H), 2.38 (s, 6H), 2.40 (s, 3H), 2.84 (t,
2H),
3.26 (s, 6H), 3.60 (q, 2H), 3.94 (t, 2H), 4.52 (t, 2H), 4.80 (m, 2H), 6.94 (d,
1 H), 8.15
(d, 1 H), .8.34 (s, 1 H). MS APCI+ m/z 457 [MH]+

Examples 11 to 41
The appropriate monochloro precursor (1 eq) was dissolved in dimethyl
sulphoxide
(1-2mLmmol-') and the solution treated with the appropriate HNR3R4 amine (3eq)
and
N-ethyldiisopropylamine (3eq). The reaction mixture was then stirred at 120 C
for 18
hours, allowed to cool to room temperature and concentrated in vacuo. The
residue
was dissolved in dichloromethane and the organic phase washed with citric acid


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solution (20mL), dried over magnesium sulphate and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel eluting with
dichloromethane:methanol 100:0 to 94:6 to yield the desired product.

Monochloro precursors from preparations 135, 136, 137, 140, 141, 142, 143,
144,
146, 147, 148, 149, 170 and 171 were used.

N
N
~N
N~ N
HO N-\ _R3
R4
Ex -NR3R4 Data

'H NMR (CD3OD, 400MHz) 6: 1.18 (t, 3H), 1.35 (t,

11 -N(CH2CH3)2 2.45 (s, 3H), 3.60 (m, 2H), 3.78 (m, 4H), 3.98 (m,
3)2
2H), 4.90 (m, 2H), 7.05 (m, 1 H), 8.10 (m, 2H). MS
APCI- m/z 412 [M-H]-

N 'H NMR (CD3OD, 400MHz) 6: 1.10 (t, 3H), 2.20 (m,
12 2H), 2.50 (s, 3H), 3.40 (s, 3H), 3.58 (m, 2H), 3.80 (m,
4H), 3.98 (t, 2H), 4.18 (s, 1 H), 4.90 (s, 2H), 7.05 (m,
O CH3 I H), 8.18 (m, 2H). MS APCI- m/z 440 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 1.10 (t, 3H), 2.20 (m,
N 2H), 2.50 (s, 3H), 3.40 (s, 3H), 3.58 (m, 2H), 3.80 (m,
13 4H), 3.98 (t, 2H), 4.18 (s, 1 H), 4.90 (s, 2H), 7.05 (m,
O-CH3 1 H), 8.05 (m, 2H), 8.15 (d, 1 H). MS APCI- m/z 440
[M-H]"

'H NMR (DMSO-D6, 400MHz) 8: 1.00 (t, 3H), 2.40 (s,
14 -N(CH3)2 3H), 3.18 (s, 6H), 3.50 (m, 2H), 3.85 (t, 2H), 4.90 (m,
2H), 7.10 (m, 1 H), 8.10 (m, 1 H), 8.25 (m, 1 H). MS
APCI- m/z 384 [M-H]-


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'H NMR (DMSO-D6, 400MHz) 8: 0.81 (t, 3H), 1.05 (t,
W CH3 3H), 1.60 (m, 2H), 2.31 (s, 3H), 3.13 (s, 3H), 3.45-
15 3.60 (m, 4H), 3.83 (t, 2H), 4.74 (t, 2H), 6.93 (d, 1 H),
CH3 8.05 (m, 1 H), 8.19 (d, 1 H), 9.73 (m, 1 H). MS APCI+
m/z 414 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 0.82 (d, 6H), 1.04 (t,
~ N~CH3 3H), 2.06 (m, 1 H), 2.38 (s, 3H), 3.14 (s, 3H), 3.45 (m,
16 CH$ 2H), 3.57 (m, 2H), 3.85 (m, 2H), 4.73 (m, 2H), 6.92

CH3 (m, 1 H), 8.06 (m, 1 H), 8.20 (m, 1 H), 9.70 (m, 1 H).
MS APCI+ m/z 428 [MH]+

~N,CH3 'H NMR (CD3OD, 400MHz) 8: 1.12 (t, 3H), 2.45 (s,
3H), 3.36 (s, 3H), 3.41 (s, 3H), 3.58 (m, 2H), 3.74 (m,
17 2H), 3.88 (m, 2H), 3.97 (m, 2H), 4.88 (m, 2H), 7.05

O, CH3 (m, 1 H), 8.09 (m, 1 H), 8.16 (m, 1 H). MS APCI- m/z
428 [M-H]-

NCH3 'H NMR (DMSO-D6, 400MHz) S: 1.04 (t, 3H), 1.15-
1.85 (m, 8H), 2.32 (s, 3H), 3.00 (s, 3H), 3.52 (q, 2H),
18 3.84 (t, 2H), 4.75 (t, 2H), 5.13 (s, 1 H), 6.92 (d, 1 H),
8.11 (m, 1 H), 8.18 (d, 1 H), 9.72 (m, 1 H). MS APCI+
m/z 440 [MH]+

N
6 N
R
\
N
N ~ I N CH3
HO N R3
-
Ra
Ex -NR3R4 R6 Data

'H NMR (CDCI3, 400MHz) 8: 0.77 (t,
~NCH3 3H), 1.24 (s, 6H), 1.59 (m, 2H),
19 H C~CH -(CH2)20(CH2)2CH3 2.37 (s, 3H), 3.02 (s, 3H), 3.56 (m,
3 3
2H), 3.95 (m, 2H), 4.80 (m, 2H),


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5.02 (m, 1 H), 6.85 (m, 1 H), 8.20 (m,
1 H), 8.25 (m, 1 H). MS ES+ m/z
450 [MNa]+

'H NMR (CDC13, 400MHz) 8: 0.74 (t,
3H), 1.26 (t, 3H), 1.49 (m, 2H), 2.40
NCH3 (s, 3H), 3.22 (s, 3H), 3.54 (m, 2H),
20 -(CH2)20(CH2)2CH3 3.75 (m, 2H), 3.97 (m, 2H), 4.82 (m,
CH3 2H), 6.88 (d, 1 H), 8.21 (d, 1 H), 8.29
(m, 1 H) . MS APCI+ m/z 426
[MH]+
'H NMR (CD3OD, 400MHz) 5: 0.74
(t, 3H), 1.49 (m, 2H), 2.12 (m, 4H),

21 N L:> -(CH2)2O(CH2)2CH 2.48 (s, 3H), 3.48 (m, 2H), 3.75 (m,
3
4H), 3.95 (m, 2H), 4.85 (m, 2H),
7.08 (d, 1 H), 8.17 (m, 1 H). MS
APCI+ m/z 428 [MH]+

'H NMR (DMSO-D6, 400MHz) 8:
1.24 (d, 6H), 2.37 (s, 3H), 3.00 (s,
CH3 3H), 3.80 (m, 2H), 4.77 (m, 2H),
22 ~N -(CH
~)ZOCH3
H3C CH3 5.00 (m, 1 H), 6.90 (m, 1 H), 8.04 (m,
1 H), 8.20 (m, 1 H), 9.80 (m, 1 H).
MS APCI- m/z 398 [M-H]-

'H NMR (DMSO-D6, 400MHz) 8:
2.34 (s, 3H), 3.12 (s, 6H), 3.31 (s,
23 -N(CH3)2 -(CH2)20CH3 3H), 3.80 (m, 2H), 4.78 (m, 2H),

6.90 (d, 1 H), 8.02 (m, 1 H), 8.20 (d,
1 H). MS APCI+ m/z 372 [M-H]+


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H3CH
N-Rl
N-~ N
N
HO N -R3
O H3C
Ex R' R3 Data

'H NMR (DMSO-D6, 400MHz) 8: 1.06 (t,
CH3 3H), 2.24 (s, 3H), 3.13 (s, 6H), 3.51 (m,
24 -CH3 2H), 3.83 (m, 2H), 4.72 (m, 2H), 7.63 (m,
1 H), 8.16 (m, 2H), 9.65 (m, 1 H). MS
ES- m/z 384 [M-H]-

'H NMR (DMSO-D6, 400MHz) S: 1.10 (t,
3H), 1.18 (d, 6H), 2.26 (s, 3H), 2.98 (s,
N~
25 CH3 -CH(CH3)2 3H), 3.58 (q, 2H), 3.90 (m, 2H), 4.77 (m,
2H), 4.99 (m, 1 H), 7.62 (m, 1 H), 8.10 (m,
1 H), 8.19 (m, 1 H). MS APCI- m/z 412
[M-H]"

CH3 'H NMR (CD3OD, 400MHz) S: 1.11 (t,
3H), 1.30 (d, 6H), 2.40 (s, 3H), 2.49 (s,
26 i -CH(CH3)2 3H), 3.10 (s, 3H), 3.55 (m, 2H), 3.93 (m,

CH3 2H), 4.90 (m, 2H), 6.90 (m, 1 H), 7.87 (m,
1 H). MS ES- m/z 426 [M-H]-

CH 'H NMR (CD3OD, 400MHz) b: 1.08 (t,
3
3H), 2.41 (s, 3H), 2.53 (s, 3H), 3.30 (s,
27 i -CH3 6H), 3.55 (m, 2H), 3.94 (m, 2H), 4.91 (m,
CH3 2H), 6.91 (m, 1 H), 7.82 (m, 1 H), . MS
ES+ m/z 400 [MH]+

N~N 'H NMR (CD3OD, 400MHz) 8: 1.22 (t,
28 -CH(CH3)Z 3H), 1.26 (d, 6H), 3.10 (s, 3H), 3.67 (q,
2H), 3.97 (t, 2H), 4.80 (t, 2H), 5.11 (m,


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1 H), 8.28 (m, 1 H), 8.61 (d, 1 H), 9.83 (s,
1 H). MS APCI+ m/z 401 [MH]+

'H NMR (CD30D, 400MHz) 8: 1.20 (t,
3H), 1.28 (d, 6H), 3.10 (s, 3H), 3.67 (q,
N
29 2H), 3.98 (t, 2H), 4.85 (m, 2H), 5.04 (m,
-CH(CH3)2 N 1 H), 5.48 (s, 2H), 8.31 (m, 1 H), 8.42 (m,

1 H), 9.48 (m, 1 H). MS APCI+ m/z 401
[MH]+

'H NMR (CD3OD, 400MHz) 8: 1.00 (t,
3H), 1.16 (t, 3H), 1.32 (m, 1 H), 1.47 (m,
30 (CH2)2CH4H), 1.74 (m, 3H), 1.88 (m, 2H), 2.14 (m,
-3
2H), 3.28 (s, 3H), 3.58 (q, 2H), 3.69 (t,
2H), 3.89 (t, 2H), 4.16 (m, 1 H), 4.70 (t,
2H). MS ES+ m/z 405 [MH]+

'H NMR (CDCI3, 400MHz) S: 0.86 (t, 3H),
1.18 (d, 6H), 1.57 (m, 2H), 1.73 (m, 2H),
31 -CH(CH3)2 1.88 (m, 2H), 2.16 (m, 2H), 2.98 (s, 3H),
3.51 (m, 2H), 3.86 (m, 2H), 4.40 (m, 1 H),
4.61 (m, 2H), 7.07 (m, 1 H). MS ES+
m/z 413 [MNa]+

'H NMR (CD3OD, 400MHz) 8: 1.19 (t,
3H), 1.31 (d, 6H), 1.96 (m, 2H), 2.22 (m,
32 -CH(CH3)2 2H), 2.52 (m, 2H), 3.12 (s, 3H), 3.57 (q,
2H), 3.90 (m, 2H), 4.65 (m, 1 H), 4.76 (m,
2H), 5.03 (m, 1 H). MS ES- m/z 375 [M-
H]"

'H NMR (CD3OD, 400MHz) 8: 1.19 (t,
3H), 1.92 (m, 2H), 2.22 (m, 2H), 2.52 (m,
33 -CH3 2H), 3.32 (s, 6H), 3.57 (q, 2H), 3.90 (m,
2H), 4.69 (m, 1 H), 4.76 (m, 2H). MS
ES- m/z 347 [M-H]"


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'H NMR (CD3OD, 400MHz) 8: 0.80 (m,
2H), 0.98 (m, 2H), 1.17 (t, 3H), 1.31 (d,

34 o"A -CH(CH3)2 6H), 3.07 (m, 1 H), 3.15 (s, 3H), 3.52 (q,
2H), 3.86 (m, 2H), 4.70 (m, 2H), 5.10 (m,
I H). MS ES- m/z 361 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 0.80 (m,
2H), 0.98 (q, 2H), 1.17 (t, 3H), 3.09 (m,
35 olA -CH3 1 H), 3.35 (s, 6H), 3.52 (q, 2H), 3.86 (m,
2H), 4.71 (m, 2H). MS ES- m/z 333 [M-
H]"

'H NMR (CD3OD, 400MHz) 8: 1.13 (t,
3H), 1.29 (m, 6H), 2.75 (q, 2H), 3.13 (s,
N
36 I -CH(CH3)2 3H), 3.60 (q, 2H), 3.96 (t, 2H), 4.88 (m,
2H), 5.10 (m, 1 H), 7.08 (d, 1 H), 8.16 (s,
CH3 1 H), 8.21 (d, 1 H). MS ES- m/z 426 [M-
H]-

'H NMR (CD3OD, 400MHz) 66: 1.11 (t,
i 3H), 1.31 (t, 3H), 2.75 (q, 2H), 3.30 (s,
37 -CH3 6H), 3.58 (q, 2H), 3.95 (t, 2H), 4.88 (m,
CH3 2H), 7.08 (d, 1 H), 8.19 (s, 1 H), 8.20 (d,
1 H). MS ES- m/z 398 [M-H]-

'H NMR (CD3OD, 400MHz) S: 1.17 (t,
CH3 3H), 1.28 (t, 3H), 2.54 (s, 3H), 3.27 (s,
38 N -CH2CH3 3H), 3.62 (q, 2H), 3.76 (q, 2H), 3.97 (t,
2H), 4.88 (t, 2H), 7.03 (d, 1 H), 7.80 (t,
1 H), 8.02 (d, 1 H). MS ES+ m/z 400
[MH]+

CH3 'H NMR (CD3OD, 400MHz) S: 1.16 (t,
39 N -CH3 3H), 2.54 (s, 3H), 3.29 (s, 6H), 3.60 (q,
2H), 3.95 (t, 2H), 4.89 (t, 2H), 7.02 (d,
1 H), 7.80 (t, 1 H), 8.02 (d, 1 H). MS ES+


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m/z 386 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.10 (t,
3H), 1.31 (t, 3H), 2.29 (s, 3H), 2.39 (s,
40 N I CH3 3H), 3.27 (s, 3H), 3.60 (q, 2H), 3.77 (q,
-CH2CH3
CH3 2H), 3.96 (t, 2H), 4.88 (t, 2H), 8.04 (s,
1 H), 8.10 (s, 1 H). MS ES+ m/z 414
[MH]+

'H NMR (CD3OD, 400MHz) 6: 1.10 (t,
N CH3 3H), 2.29 (s, 3H), 2.39 (s, 3H), 3.30 (s,
41 -CH3 3H), 3.31 (s, 3H), 3.58 (q, 2H), 3.94 (q,
CH3 2H), 4.85 (t, 2H), 8.03 (s, 1 H), 8.06 (s,
1 H). MS ES+ m/z 400 [MH]+

= Examples 14 and 24-31 were performed without N-ethyldiisopropylamine
= Examples 38-41 were performed using caesium fluoride instead of N-
ethyldiisopropylamine

= Example 12 used the amine of preparation 4 as the HNR3R4 amine
= Example 13 used the amine of preparation 3 as the HNR3R4 amine
Examples 42 to 48

H3CO N
~N
N\ \ N

HO N--~ _R3
,
O N
R4
The monochloro compound of preparation 144 (99mg, 0.27mmol) was dissolved in
dimethyl sulphoxide (3mL) and the solution treated with the appropriate HNR3R4

amine (1.08mmol). The reaction mixture was heated to 120 C for 18 hours before
being allowed to cool to room temperature. The reaction mixture was diluted
with
dichloromethane and washed with water, brine (x2) and citric acid. The
dichloromethane phase was dried over magnesium sulphate and concentrated in
vacuo. The residue was purified by column chromatography on silica gel eluting
with


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dichloromethane:methanol 100:0 to 85:15. The crude product was triturated with
ether to give the desired product.

Ex -NR3R4 Data

'H NMR (CD30D, 400MHz) 8: 1.16 (t, 3H), 1.30 (m,

42 -N(CH3)2 H), 1.48 (m, 4H), 1.72 (m, 1 H), 1.86 (m, 2H), 2.15 (m,
3)~
2H), 3.30 (s, 6H), 3.58 (q, 2H), 3.89 (t, 2H), 4.20 (m,
I H), 4.70 (t, 2H). MS ES+ m/z 375 [MH]+

'H NMR (CD3OD, 400MHz) S: 1.16 (t, 3H), 1.29 (t, 4H),
43 NCH3 1.48 (m, 4H), 1.73 (m, 1H), 1.86 (m, 2H), 2.14 (m, 2H),
CH3 3.27 (s, 3H), 3.58 (q, 2H), 3.77 (q, 2H), 3.90 (t, 2H),
4.19 (m, 1 H), 4.71 (t, 2H). MS ES+ m/z 389 [MH]+
'H NMR (CD3OD, 400MHz) 5: 1.16 (t, 3H), 1.31 (m,

44 N 1 H), 1.48 (m, 4H), 1.73 (m, 1 H), 1.86 (m, 2H), 2.13 (m,
6H), 3.58 (q, 2H), 3.71 (m, 4H), 3.90 (t, 2H), 4.21 (m,
1 H), 4.71 (t, 2H). MS ES+ m/z 401 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.17 (t, 3H), 1.30 (t, 4H),
45 -NHCH2CH3 (m, 4H), 1.73 (m, 1 H), 1.86 (m, 2H), 2.14 (m, 2H),
3
3.57 (m, 4H), 3.90 (t, 2H), 4.23 (m, 1 H), 4.70 (t, 2H).
MS ES+ m/z 375 [MH]+

'H NMR (CD3OD, 400MHz) 6: 1.16 (t, 3H), 1.30 (d, 7H),
46 ~ NCH3 1.48 (m, 4H), 1.72 (m, 1 H), 1.87 (m, 2H), 2.14 (m, 2H),
H3C CH3 3.12 (s, 3H), 3.58 (q, 2H), 3.90 (t, 2H), 4.16 (m, 1 H),
4.70 (t, 2H), 4.95 (m, 1 H). MS ES+ m/z 403 [MH]+

'H NMR (CD3OD, 400MHz) 5: 1.16 (t, 3H), 1.32 (t, 7H),
47 -N(CH2CH3)2 (m, 4H), 1.72 (m, 1 H), 1.86 (m, 2H), 2.13 (m, 2H),
2
3.58 (q, 2H), 3.72 (q, 4H), 3.90 (t, 2H), 4.17 (m, 1 H),
4.71 (t, 2H). MS ES+ m/z 403 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.15 (t, 3H), 1.32 (m,
48 -NHCH3 1 H), 1.47 (m, 4H), 1.72 (m, 1 H), 1.85 (m, 2H), 2.16 (m,
2H), 3.05 (s, 3H), 3.56 (q, 2H), 3.89 (m, 2H), 4.22 (m,


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1 H), 4.72 (m, 2H). MS ES+ m/z 367 [MH]+

Examples 49 to 74
6 R 1
R ~N-R2
N~ N
HO N~
N-R3
R 4

The appropriate monochloro precursor (0.266mmol) and tetraethylammonium
fluoride (39.6mg, 0.266mmol) were dissolved in dimethyl sulphoxide (1.OmL) and
the
solution treated with N-ethyldiisopropylamine (230 L, 1.33mmol) and a solution
of

the appropriate HNR3R4 amine (1.33mmol) in dimethyl sulphoxide (500 L). The
reaction mixture was placed in a sealed vessel and shaken at 350rpm at 120 C
for
18 hours. The reaction mixture was diluted with dichloromethane and washed
with
I M citric acid solution and water. The dichloromethane phase was then dried
over
magnesium sulphate and concentrated in vacuo. The residue was purified by
column chromatography on silica gel eluting with dichloromethane:methanol
100:0 to
90:10 to yield the desired product.

Monochloro precursors from preparations 137, 138, 139, 145, 150, 151; 172, 173
and 174 were used.

H3C0 H
~
N~ / \ N CH3

HO N `R3
N
R4
Ex -NR3R4 Data


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'H NMR (CD3OD, 400MHz) 8: 0.40 (q, 2H), 0.60 (q,
N 2H), 1.00 (t, 3H), 1.14 (t, 3H), 1.23 (m, 1 H), 1.78 (q,
49 2H), 2.47 (q, 2H), 3.60 (m, 4H), 3.69 (m, 2H), 3.96 (t,
CH3 2H), 4.88 (m, 2H), 7.03 (d, 1 H), 8.16 (m, 2H). MS ES+
m/z 454 [MH]+

'H NMR (CD3OD, 400MHz) 8: 0.93 (t, 3H), 1.14 (t, 3H),
~N~CH3 1.29 (d, 3H), 1.69 (m, 2H), 2.46 (s, 3H), 3.11 (s, 3H),
50 CH 3.33 (m, 1 H), 3.61 (m, 2H), 3.95 (t, 2H), 4.88 (m, 2H),
3 7.04 (d, 1 H), 8.15 (s, 1 H), 8.17 (d, 1 H). MS ES+ m/z
CH3
428 [MH]+

~N,CH3 'H NMR (CD3OD, 400MHz) b: 1.12 (t, 3H), 1.81 (m,
51 2H), 2.35 (m, 4H), 2.48 (s, 3H), 3.24 (s, 3H), 3.33 (m,
1 H), 3.59 (m, 2H), 3.95 (t, 2H), 4.88 (m, 2H), 7.04 (d,
1 H), 8.16 (m, 2H). MS ES+ m/z 426 [MH]+

NCH3 'H NMR (CD3OD, 400MHz) 8: 1.13 (t, 3H), 1.34 (t, 3H),
52 2.47 (s, 3H), 3.44 (s, 3H), 3.60 (m, 2H), 3.74-3.84 (m,
6H), 3.96 (t, 2H), 4.89 (m, 2H), 7.05 (d, 1 H), 8.12 (s,
O~CH3 1 H), 8.16 (d, 1 H). MS ES+ m/z 444 [MH]+

CH3 'H NMR (CD3OD, 400MHz) 8: 1.12 (t, 3H), 1.39 (d, 3H),
53 1.87 (m, 1 H), 2.23 (m, 3H), 2.48 (s, 3H), 3.60 (m, 3H),
N
3.80 (m, 1 H), 3.96 (t, 2H), 4.46 (m, 1 H), 4.89 (m, 2H),
7.07 (d, 1 H), 8.18 (m, 2H). MS ES+ m/z 426 [MH]+

'H NMR (CD3OD, 400MHz) S: 1.11 (t, 3H), 1.35 (d, 6H),
CH3 2.54 (s, 3H), 3.55 (m, 2H), 3.98 (t, 2H), 4.18 (m, 1 H),
54 ~NCH
H 3 5.03 (t, 2H), 7.16 (d, 1 H), 8.10 (s, 1 H), 8.12 (d, 1 H).
MS ES+ m/z 400 [MH]+

Y\ NH 'H NMR (CD3OD, 400MHz) 8: 1.00 (t, 3H), 1.10 (t, 3H),
55 1.30 (t, 3H), 1.67 (m, 2H), 2.53 (s, 3H), 3.54 (m, 2H),
CH3 3.98 (m, 3H), 5.02 (t, 2H), 7.17 (d, 1 H), 8.10 (s, 1 H),
CH3 8.13 (d, 1 H). MS ES+ m/z 414 [MH]+


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NH 'H NMR (CD3OD, 400MHz) 6: 1.00 (t, 3H), 1.10 (t, 3H),
= 1.30 (t, 3H), 1.67 (m, 2H), 2.53 (s, 3H), 3.54 (m, 2H),
56
~CH3 3.98 (m, 3H), 5.02 (t, 2H), 7.17 (d, 1 H), 8.10 (s, 1 H),
CH3 8.13 (d, 1 H). MS ES+ m/z 414 [MH]+

N
6 N
R
N N CH3
HO N~ N-R3

R 4
Ex -NR3R4 R6 Data

'H NMR (CD3OD, 400MHz) 8: 1.47
(m, 4H), 2.30 (m, 1 H), 2.50 (s, 3H),
3.28 (s, 6H), 3.36 (m, 2H), 3.90 (m,
57 -N(CH3)2 O CH2 2H), 4.70 (d, 2H), 7.08 (d, 1 H),
7.80 (s, 1 H), 8.10 (d, 1 H). MS
APCI+ m/z 412 [MH]+

'H NMR (CD3OD, 400MHz) b: 1.28
(t, 3H), 1.44 (m, 4H), 2.30 (m, I H),
4-1 N,CH3 O 2.48 (s, 3H), 3.24 (s, 3H), 3.34 (m,
58 CH 2H), 3.73 (q, 2H), 3.90 (m, 2H),
CH3 2 4.70 (d, 2H), 7.07 (d, 1 H), 7.84 (s,
I H), 8.08 (d, 1 H). MS APCI+ m/z
426 [MH]+

'H NMR (DMSO-D6, 400MHz) b:
1.20 (rri, 1 H), 1.50 (m, 3H), 1.74
a 0 (m, 1 H), 1.82 (m, 1 H), 2.35 (s, 3H),
59 -N(CH3)2 CH 3.14 (s, 6H), 3.46 (m, 1 H), 3.84 (m,
2
1 H), 4.06 (m, 1 H), 4.58 (m, 1 H),
4.70 (m, 1 H), 6.92 (d, 1 H), 8.08 (m,
1 H), 8.19 (m, 1 H). MS APCI+ m/z


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412 [MH]+

'H NMR (DMSO-D6, 400MHz) b:
1.17 (t, 3H), 1.20 (m, 1 H), 1.47 (m,
N/CH3 O 3H), 1.78 (m, 2H), 2.32 (s, 3H),

60 3.12 (s, 3H), 3.42 (m, 1 H), 3.68 (m,
CH3 CH2 2H), 3.84 (m, 1 H), 4.07 (m, 1 H),
4.58 (m, 1 H), 4.68 (m, 1 H), 6.95 (d,
1 H), 8.05 (m, 1 H), 8.20 (m, 1 H).
MS APCI+ m/z 426 [MH]+

'H NMR (CD3OD, 400MHz) S: 1.06
(m, 6H), 2.42 (s, 3H), 3.27 (s, 6H),
61 -N(CH3)2 -(CH2)2OCH(CH3)2 3.67 (m, 1 H), 3.94 (t, 2H), 4.82 (m,
2H), 7.07 (d, 1 H), 8.17 (m, 2H).
MS APCI+ m/z 400 [MH]+

'H NMR (CD3OD, 400MHz) S: 1.08
(d, 6H), 1.27 (t, 3H), 2.43 (s, 3H),
N~CH3
62 -(CH2)20CH(CH3) 3.28 (s, 3H), 3.65 (m, 1 H), 3.80 (q,
2
CH3 2H), 3.95 (t, 2H), 4.85 (m, 2H),
7.06 (d, 1 H), 8.20 (m, 2H). MS
APCI+ m/z 414 [MH]+

'H NMR (DMSO-D6, 400MHz) 5:
0.97 (d, 6H), 1.16 (t, 3H), 2.44 (s,
63 -NHCH2CH3 -(CH2)20CH(CH3)2 3H), 3.37 (m, 2H), 3.50 (m, 1 H),
3.81 (t, 2H), 4.90 (t, 2H), 7.05 (d,
1 H), 8.08 (s, 1 H), 8.22 (d, 1 H). MS
APCI+ m/z 400 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.28
O~CH3 (d, 3H), 2.45 (s, 3H), 3.30 (s, 6H),
64 -N(CH3)2 H CCH 3.42 (s, 3H), 3.98 (m, 1 H), 4.74 (m,
3 2 2H), 7.03 (d, 1 H), 8.08 (m, 1 H),
8.18 (m, 1 H). MS APCI+ m/z 386


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[MH]+
'H NMR (CD30D, 400MHz) S: 1.32

N/CH3 0 CH3 (m, 6H), 2.45 (s, 3H), 3.36 (s, 3H),
65 ~ 3.42 (s, 3H), 3.78 (q, 2H), 4.00 (m,
CH3 H3C CH2 1 H), 4.74 (m, 2H), 7.04 (d, 1 H),
8.10 (m, 1 H), 8.20 (m, 1 H). MS
APCI+ m/z 400 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.30
0 CH3 (m, 9H), 2.45 (s, 3H), 3.44 (s, 3H),
66 -N(CH2CH3)2 3.64 (q, 2H), 4.00 (m, 1 H), 4.72 (m,
H3C CH2 2H), 7.03 (m, 1 H), 8.11 (m, 1 H),
8.19 (m, 1 H). MS APCI+ m/z 414
[MH]+

H3CO-"~ N_Rl
~N
N~ N

HO N _Rs
,
0 N
R4
Ex R' -NR3R4 Data

'H NMR (DMSO-D6, 400MHz) 8: 1.03
p N/CH3 (t, 3H), 1.23 (d, 6H), 2.09 (m, 1 H),
2.33 (m, 1 H), 3.07 (s, 3H), 3.44 (q,
67
H3C CH3 2H), 3.77 (m, 2H), 3.95 (m, 2H), 4.75
(m, 2H), 4.84 (m, 2H). MS ES+ m/z
393 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 1.04
p (t, 3H), 1.22 (t, 6H), 2.09 (m, 1 H), 2.32
68 -N(CHZCH3)2 (m, 1 H), 3.44 (q, 2H), 3.77 (m, 8H),
3.94 (m, 2H), 4.75 (m, 1 H), 4.84 (m,
2H). MS ES+ m/z 393 [MH]+


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'H NMR (CD3OD, 400MHz) 8: 1.16 (t,

O ~N~CH 3H), 1.84 (m, 2H), 2.09 (m, 1 H), 2.35
3
69 (m, 4H), 2.48 (m, 1 H), 3.26 (s, 3H),
3.58 (q, 2H), 3.89 (m, 4H), 4.05 (m,
2H), 4.73 (t, 2H), 4.85 (m, 2H). MS
ES+ m/z 405 [MH]+

'H NMR (CDCI3, 400MHz) 8: 1.25 (m,
OCH3 N,CH3 6H), 3.22 (s, 3H), 3.70 (m, 4H), 3.99 (t,
70 N"~N CH 2H), 4.01 (s, 3H), 4.80 (t, 2H), 7.90 (d,
~ 3 1 H), 8.42 (d, 1 H), 10.18 (s, 1 H). MS
APCI- m/z 415 [M-H]"

'H NMR (CDC13, 400MHz) 6: 1.25 (t,
O~CH3 3H), 3.30 (s, 6H), 3.70 (q, 2H), 3.99 (t,
71 NI~N -N(CH3)2 2H), 4.02 (s, 3H), 4.80 (t, 2H), 8.42 (d,
~ 1 H), 8.45 (d, 1 H), 10.18 (s, 1 H). MS
APCI- m/z 401 [M-H]"

'H NMR (CD3OD, 400MHz) 8: 1.24 (t,
CH3 N-1 N,CH3 3H), 1.28 (d, 6H), 2.60 (s, 3H), 3.10 (s,
72 NI ~ N 3H), 3.69 (q, 2H), 3.99 (t, 2H), 4.82 (t,
H3CCH3 2H), 5.09 (m, 1 H), 8.09 (d, 1 H), 8.51
(m, 1 H). MS ES- m/z 413 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 1.23 (t,
CH3 *11 N,CH3 6H), 2.60 (s, 3H), 3.23 (s, 3H), 3.71 (q,
73 N N 2H), 3.78 (q, 2H), 3.98 (t, 2H), 4.81 (t,
CH3 2H), 8.11 (d, 1 H), 8.51 (m, 1 H). MS
ES- m/z 399 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 1.25 (m,
~j'H3
I NCH3 6H), 2.45 (s, 6H), 3.25 (s, 3H) 3.61 (q,
74 i~ N 2H), 3.78 (q, 2H), 3.98 (t, 2H), 4.90 (t,
~'\~CH
3 CH3 2H), 6.99 (d, 1 H). MS ES- m/z 413
[M-H]"


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= Example 51 was prepared using cyclobutyl-methyl-amine (J. Med. Chem.,
1994, 37, 3482-3491) as the HNR3R4 amine.

= Examples 67, 68 and 69 were purified by column chromatography on silica
gel eluting with dichloromethane:methanol:acetic acid 90:10:1

= Examples 70 and 71 were prepared without the use of N-
ethyldiisopropylamine.

Example 75
3-('1-(2-Ethoxyethyl)-5-(N-isopropyl-N-meth la)-7-(4-methylpyridin-2-ylamino)-
1 H-pyrazolo[4,3-d]pyrimidin-3-yl1-2H-1,2,4-oxadiazol-5-one

H3C~~C N

N N CH3
C''H3
N N: ~ N
05~~ O11NH H C CH3
3
The oxadiazolone of preparation 183 (50mg, 0.12mmol) was added to a solution
of
methylisopropylamine (44mg, 0.60mmol) and N-ethyldiisopropylamine (83 L,
0.60mmol) in dimethyl sulphoxide (1 mL) and the reaction mixture stirred at
120 C for
18 hours. The reaction mixture was diluted with ethyl acetate (20mL) and
washed
with water (15mL). The aqueous phase was then extracted with ethyl acetate
(2x2OmL), acidified with acetic acid solution and extracted with further ethyl
acetate
(2x2OmL). The organics were combined, dried over magnesium sulphate and
concentrated in vacuo. The residue was purified by column chromatography on
silica
gel eluting with dichloromethane:methanol:acetic acid 100:0:0 to 97.5:2.5:0.25
to
yield the title product.

'H NMR (CD3OD, 400MHz) 8: 1.11 (t, 3H), 1.25 (d, 6H), 2.41 (s, 3H), 3.09 (s,
3H),
3.60 (m, 2H), 3.95 (t, 2H), 4.83 (t, 2H), 5.16 (m, 1 H), 6.95 (d, 1 H), 8.16
(m, 1 H), 8.25
(m, 1 H)
MS ES+ m/z 454 [MH]+


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The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for example 75 using the monochloro precursor
from preparations 183, 184 and 185.

N ~
H3C0 N R
.
N~ N/ N CH3
R5 N N_R3

R4
H3CO N-R1
~N
N N
N- N
N
O~ NH R4 CH3
O

Ex R' R4 Data

'H NMR (CD3OD, 400MHz) S: 1.12 (t, 3H),
N 1.25 (t, 3H), 2.41 (s, 3H), 3.24 (s, 3H),
76 1 -CH3 3.61 (m, 2H), 3.77 (m, 2H), 3.94 (t, 2H),
CH3 4.84 (t, 2H), 6.95 (d, 1 H), 8.16 (s, 1 H),
8.31 (m, I H). MS ES+ m/z 440 [MH]+
'H NMR (DMSO-D6, 400MHz) S: 0.99 (t,

F 3H), 1.10 (t, 3H), 2.26 (s, 3H), 3.07 (s,
~
77 ~/ -CH3 3H), 3.50 (q, 2H), 3.58 (q, 2H), 3.84 (m,
CH3 2H), 4.84 (m, 2H), 7.14 (t, 1 H), 7.47 (m,
1 H), 7.68 (m, 1 H), ,8.87 (s, 1 H),. MS ES+
m/z 457 [MH]+


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'H NMR (DMSO-D6, 400MHz) 6: 1.00 (t,

F 3H), 1.10 (t, 6H), 2.25 (s, 3H), 3.50 (q,
~CH 2H), 3.58 (q, 4H), 3.84 (m, 2H), 4.84 (m,
78 I/ -CHaCH3 2H), 7.15 (t, 1 H), 7.40 (m, 1 H), 7.69 (m,
3
1 H), 8.85 (s, 1 H). MS APCI- m/z 469 [M-
H]-

N-
H3CO N \ ~
N N CH3
N- N~ R3
N-N~~ "INH
N H3C
R3

'H NMR (CD3OD, 400MHz) 8: 1.13 (t, 3H), 1.25 (d, 6H),
79 -CH(CH 2.42 (s, 3H), 3.12 (s, 3H), 3.61 (m, 2H), 3.95 (m, 2H), 4.84
3)2
(m, 2H), 5.20 (m, 1 H), 6.95 (d, 1 H), 8.15 (m, 1 H), 8.30 (m,
I H). MS ES- m/z 436 [M-H]-

'H NMR (CD3OD, 400MHz) 5: 1.13 (t, 3H), 2.44 (s, 3H), 3.30
80 -CH3 (s, 6H), 3.61 (m, 2H), 3.72 (t, 2H), 4.90 (t, 2H), 7.00 (d, 1 H),
8.17 (m, 1 H), 8.25 (m, 1 H). MS APCI+ m/z 410 [MH]+

Example 81
1-(2-Ethoxyeth r~l -7-(5-fluoropyridin-2-ylamino)-5-(N-isopropyl-N-meth lay
mino)-1H-
pyrazolo[4,3-d]pyrimidine-3-carboxylic acid

N-
H3C/~O N \ / F
,1N
N~ / ~ N

HO N- CH3
O H C CH3
3


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The ester of preparation 108 (30mg, 0.07mmol) and a 1 M aqueous solution of
sodium hydroxide (105 L, 0.105mmol) were dissolved in dioxane (1 mL) and the
reaction mixture stirred at room temperature for 18 hours. The reaction
mixture was
concentrated in vacuo and the residue treated with I M citric acid solution
(5mL) and
extracted with dichloromethane (3x5OmL). The organics were combined, dried
over
sodium sulphate and concentrated in vacuo. The crude product was triturated
with
ether and then filtered to yield the title product as a white solid, 27mg.

'H NMR (CD3OD, 400MHz) 8: 1.22 (t, 3H), 1.30 (d, 6H), 3.12 (s, 3H), 3.70 (q,
2H),
3.98 (t, 2H), 4.84 (t, 2H), 5.01 (m, 1 H), 7.71 (m, 1 H), 8.29 (m, 1 H), 8.31
(d, 1 H)
MS ES- m/z 416 [M-H]-

The following compounds, of the general formula shown below, were prepared by
a
method similar to that described for example 81 using the appropriate ester of
preparations 103, 106, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,
119,
121, 122, 123, 124, 125, 126, 128, 129, 130, 131, 132, 133, 134 and example 6.
H3C0-") N-R1
~N
N / \ N
HO N~ R3
N-"
O R 4

Ex R' -NR3R4 Data

'H NMR (CD3OD, 400MHz) 8: 1.16 (t,
3H), 1.78 (m, 2H), 2.14 (m, 2H), 3.32
82 -N(CH3)2 (s, 6H), 3.59 (m, 4H), 3.90 (t, 2H),
4.04 (m, 2H), 4.40 (m, 1 H), 4.74 (t,
2H). MS ES- m/z 377 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 1.19 (t,
83 O N~CH3 3H), 1.32 (d, 6H), 1.85 (m, 2H), 2.10
H3C CH3 (m, 2H), 3.16 (s, 3H), 3.60 (m, 4H),
3.93 (t, 2H), 4.05 (t, 2H), 4.45 (m, I H),


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4.89 (t, 2H), 5.01 (m, 1 H). MS ES-
m/z 405 [M-H]"

'H NMR (CD3OD, 400MHz) 8: 1.15 (t,
0 CH3 ~ 3H), 2.40 (d, 6H), 3.05 (s, 3H), 3.65
84 N N, CH3
(q, 2H), 3.95 (s, 3H), 3.98 (q, 2H),
H3C CH3 4.78 (t, 2H), 5.01 (m, 1 H), 6.49 (d,
1 H), 7.66 (t, 1 H), 7.82 (d, 1 H). MS
ES- m/z 428 [M-H]"

'H NMR (CD3OD, 400MHz) 8: 1.13 (t,
CH3 N/CH 3H), 1.26 (d, 6H), 2.33 (s, 3H), 3.11
85 F 3(s, 3H), 3.61 (q, 2H), 3.98 (t, 2H), 4.88
H3C CH3 (t, 2H), 4.90 (m, 1 H), 7.10 (t, 1 H), 7.42
(m, 1 H), 7.60 (m, 1 H). MS ES+ m/z
431 [MH]+

'H NMR (DMSO-D6, 400MHz) 8: 1.00
CH3 (t, 3H), 1.15 (t, 6H), 2.25 (s, 3H), 3.45
86 F -N(CH2CH3)2 (m, 4H), 3.50 (m, 2H), 3.82 (t, 2H),
4.81 (t, 2H), 7.08 (t, 1 H), 7.41 (m, 1 H),
7.70 (m, 1 H). MS APCI- m/z 429 [M-
H]-

'H NMR (CD3OD, 400MHz) 8: 1.10 (t,
CH3 ~ CH 3H), 1.25 (t, 3H), 2.30 (s, 3H), 3.20 (s,
87 F N 3 3H), 3.60 (q, 2H), 3.70 (q, 2H), 3.98 (t,

CH3 2H), 4.82 (m, 2H), 7.15 (t, 1 H), 7.50 (t,
1 H), 7.63 (m, 1 H). MS APCI+ m/z
439 [MNa]+

'H NMR (CD3OD, 400MHz) 8: 1.15 {t,
F 't\ N,CH3 3H), 1.31 (d, 6H), 3.17 (s, 3H), 3.64
88 JJ I\ (q, 2H), 3.99 (t, 2H), 4.89 (m, 1 H),
/ H3C CH3 4.96 (t, 2H), 7.08 (m, 1 H), 7.43 (m,

1 H), 7.51 (m, 1 H), 7.62 (m, 1 H). MS


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ES- m/z 415 [M-H]-

'H NMR (CDCI3, 400MHz) 8: 1.10 (m,
F F ~ NCH3 9H), 2.98 (s, 3H), 3.62 (q, 2H), 3.95
89 1\ (m, 2H), 4.78 (m, 2H), 4.90 (m, 1 H),
H3C/CH3 6.95 (m, 2H), 8.15 (m, 1 H), 9.01 (s,
1 H). MS APCI- m/z 453 [M-H]"

'H NMR (CDCI3, 400MHz) 8: 1.22 (m,
F
F NCH3 9H), 3.01 (s, 3H), 3.65 (q, 2H), 4.00
90 )~", (m, 2H), 4.78 (m, 2H), 4.98 (m, 1 H),
H3C CH3 7.18 (m, 2H), 7.82 (m, 1 H), 9.20 (m,
I H). MS APCI- m/z 433 [M-H]"

'H NMR (CDCI3, 400MHz) 8: 1.20 (m,
F
NCH3 9H), 3.02 (s, 3H), 3.65 (q, 2H), 4.00 (t,
91 2H), 4.78 (t, 2H), 4.98 (m, 1 H), 6.58
H3C CH3
F (m, 1 H), 7.30 (m, 2H), 9.35 (m, 1 H).
MS APCI- m/z 433 [M-H]"

'H NMR (CDCI3, 400MHz) 6: 1.18 (t,
3H), 1.28 (m, 6H), 3.05 (s, 3H), 3.62
F N~CH3
92 (q, 2H), 3.98 (t, 2H), 4.78 (t, 2H), 4.99
F H3C CH3 (m, 1 H), 6.78 (m, 1 H), 7.10 (m, 1 H),
8.25 (m, 1 H), 9.26 (m, 1 H). MS
APCI+ m/z 435 [MH]+

'H NMR (CDCI3, 400MHz) 8: 1.20 (m,
F 9H), 3.00 (s, 3H), 3.65 (q, 2H), 3.98 (t,
93 F ~ N, CH3 2H), 4.79 (t, 2H), 4.90 (m, I H), 6.95

H3C CH3 (m, 1 H), 7.10 (m, 1 H), 8.01 (m, 1 H),
9.22 (m, I H). MS APCI- m/z 433 [M-
H]"


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'H NMR (CD3OD, 400MHz) 8: 1.15 (t,

CH3 CH3H), 1.30 (d, 6H), 2.42 (s, 3H), 3.15
94 N3
(s, 3H), 3.64 (q, 2H), 4.00 (t, 2H), 4.88
H3C CH3 (m, 1 H), 4.94 (m, 2H), 7.16 (d, 1 H),
7.34 (t, 1 H), 7.42 (d, 1 H), 7.57 (s, 1 H),
MS ES- m/z 411 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 1.15 (t,
N,CH3 3H), 1.23 (d, 6H), 3.05 (s, 3H), 3.65
95 1 (q, 2H), 4.00 (t, 2H), 4.79 (t, 2H), 5.11
H3C/\CH3 (m, 1 H), 7.09 (t, 1 H), 7.40 (t, 2H), 7.71
(d, 2H). MS ES- m/z 397 [M-H]-

'H NMR (CD3OD, 400MHz) b: 1.12 (t,
3H), 1.30 (t, 3H), 2.41 (s, 3H), 3.22 (s,
96 N 11 N~CH3 3H), 3.58 (q, 2H), 3.76 (q, 2H), 3.97 (t,
CH3 CH3 2H), 4.82 (t, 2H), 7.02 (d, 1 H), 8.12 (s,
1 H), 8.14 (d, 1 H). MS APCI+ m/z 400
[MH]+

'H NMR (CDCI3, 400MHz) 6: 1.20-1.40
CH3 (m, 9H), 2.78 (q, 2H), 3.20 (s, 3H),
~ N, CH3 3.70 (m, 4H), 4.00 (t, 2H), 4.81 (t, 2H),
97 N
CH3 6.87 (d, 1 H), 7.62 (t, 1 H), 8.10 (d, 1 H),
9.85 (s, 1 H). MS APCI+ m/z 414
[MH]+

'H NMR (CDCI3, 400MHz) 8: 1.30 (m,
CH3 6H), 2.78 (q, 2H), 3.25 (s, 6H), 3.70
98 N -N(CH3)2 (q, 2H), 4.00 (m, 2H), 4.82 (m, 2H),
6.90 (d, 1 H), 7.65 (t, 1 H), 8.10 (d, 1 H),
9.90 (m, 1 H). MS APCI+ m/z 400
[MH]+


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'H NMR (CD3OD, 400MHz) 8: 1.17 (t,

CH3 ~ ,CH3 3H), 1.30 (d, 6H), 2.53 (s, 3H), 3.12
99 N N
(s, 3H), 3.65 (q, 2H), 3.97 (t, 2H), 4.89
~ H3C~CH3 (t, 2H), 4.96 (m, 1 H), 7.06 (d, I H),
7.84 (t, 1 H), 7.99 (d, 1 H). MS ES- m/z
412 [M-H]"

CH 'H NMR (CD3OD, 400MHz) 8: 1.10 (t,
3
3H), 2.37 (s, 3H), 3.23 (s, 6H), 3.61
100 / -N(CH3)2 (q, 2H), 3.96 (t, 2H), 4.85 (t, 2H), 7.08
(m, 1 H), 7.14 (m, 1 H), 7.86 (d,.1 H).
F MS ES+ m/z 403 [MH]+

'H NMR (CD3OD, 400MHz) 6: 1.11 (t,
1H3 3H), 1.20 (t, 3H), 2.38 (s, 3H), 3.23 (s,
101 I ~ N~CH3 3H), 3.59 (q, 2H), 3.61 (q, 2H), 3.95 (t,
I
/ / CH3 2H), 4.85 (t, 2H), 7.09 (m, 1 H), 7.14
F (m, 1 H), 7.84 (d, 1 H). MS ES+ m/z
417 [MH]+

'H NMR (CD3OD, 400MHz) 5: 1.12 (t,
CH3 3H), 2.30 (s, 3H), 2.32 (s, 3H), 3.29
102 CH3 -N(CH3)2 (s, 6H), 3.63 (q, 2H), 3.98 (t, 2H), 4.84
(t, 2H), 7.21 (d, 1 H), 7.45 (d, 1 H), 7.53
(s, I H). MS ES+ m/z 399 [MH]+

'H NMR (CD3OD, 400MHz) 8: 1.02 (t,
CH3 CH 3H), 1.16 (t, 3H), 2.19 (s, 3H), 2.21 (s,
103 ~ CH3 N 3 3H), 3.16 (s, 3H), 3.52 (q, 2H), 3.63
CH3 (q, 2H), 3.87 (t, 2H), 4.73 (t, 2H), 7.09
(d, 1 H), 7.30 (d, 1 H), 7.43 (m, 1 H).
MS ES+ m/z 413 [MH]+

F N,CH3 'H NMR (CD3OD, 400MHz) 8: 1.11 (t,
104 3H), 1.21 (d, 6H), 3.06 (s, 3H), 3.61
H3C CH3 (q, 2H), 3.96 (t, 2H), 4.83 (m, I H),


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4.85 (t, 2H), 7.28 (m, 3H), 7.90 (t, 1 H).
MS ES- m/z 415 [M-H]-

'H NMR (CD3OD, 400MHz) 8: 1.17 (t,
3H), 1.31 (d, 6H), 3.13 (s, 3H), 3.66
~ NCH3
105 ~ )", (q, 2H), 3.98 (t, 2H), 4.88 (t, 2H), 4.99
~ H3C CH3 (m, 1 H), 7.19 (t, 1 H), 7.90 (t, 1 H), 8.22
(d, I H), 8.35 (d, 1 H). MS ES- m/z 398
[M-H]-

N
R 6 N

N~N N CH3
~ ~

HO N~ -R3
O H3C
R3 R6 Data

'H NMR (CD3OD, 400MHz) S:
1.30 (d, 6H), 2.42 (s, 3H), 3.02 (s,
3H), 3.10 (s, 3H), 3.30 (s, 1 H),
106 -CH(CH3)2 -(CH2)20(CH2)20CH3 3.45 (t, 2H), 3.62 (t, 2H), 4.00 (t,
2H), 4.98 (m, 2H), 7.05 (d, 1 H),
8.10 (d, 1 H), 8.20 (m, 1 H). MS
APCI+ m/z 458 [MH]+

'H NMR (CD3OD, 400MHz) S:
1.18 (d, 3H), 1.35 (d, 6H), 2.10
(m, 2H), 2.50 (s, 3H), 3.10 (s,
107 -CH(CH3)2 -(CH2)2CH(CH3)OCH3 3H), 3.32 (s, 3H), 3.38 (m, 1 H),
4.80-4.90 (m, 3H), 7.10 (d, 1 H),
7.90 (s, 1 H), 8.10 (d, 1 H). MS
APCI+ m/z 428 [MH]+


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'H NMR (CD3OD, 400MHz) 8:
0.12 (m, 2H), 0.37 (m, 2H), 1.06
(m, 1 H), 1.30 (d, 6H), 2.44 (s,
~
108 -CH(CH3)2 O CH2 3H), 3.09 (s, 3H), 3.44 (d, 2H),
4.04 (t, 2H), 4.91 (m, 2H), 5.13
(m, 1 H), 7.02 (d, 1 H), 8.23 (m,
2H). MS ES- m/z 438 [M-H]"
'H NMR (CD3OD, 400MHz) 6:
0.75 (m, 2H), 0.81 (m, 2H), 0.99
(m, 1 H), 1.31 (t, 3H), 2.44 (s, 3H),
109 -CH2CH3 O CH~ 3.27 (s, 3H), 3.38 (d, 2H), 3.79 (q,
2H), 4.01 (m, 2H), 4.89 (m, 2H),
7.03 (d, 1 H), 8.19 (m, 2H). MS
ES+ m/z 426 [MH]+

Example 110
1-(2-Ethoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2- lamino)-
1 H-
pyrazolo[4,3-d]pyrimidine-3-carbox lic acid

H3C~0 N
N~ N CH3
CH3
HO N 1
O H C -\CH3
3
The ester of preparation 121 (219mg, 0.51 mmol) was dissolved in a solution of
1 M
aqueous sodium hydroxide solution (3mL) in dioxane (1.5mL) and the reaction
mixture stirred at room temperature for 18 hours. The reaction mixture was
diluted
with 1 M citric acid solution (50mL) and the mixture washed with
dichloromethane
(3x100mL). The combined dichloromethane extracts were dried over magnesium
sulphate and concentrated in vacuo. The residue was purified by column


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chromatography on silica gel eluting with dichloromethane:methanol 100:0 to
92:8 to
yield the title product as a yellow oil, 80mg (38%).

'H NMR (CD3OD, 400MHz) 5: 1.12 (t, 3H), 1.30 (d, 6H), 2.45 (s, 3H), 3.12 (s,
3H),
3.60 (m, 2H), 3.96 (t, 2H), 4.88 (m, 2H), 4.98 (m, 1 H), 7.04 (d, 1 H), 8.14
(s, 1 H), 8.18
(d, I H). MS APCI- m/z 412 [M-H]-

Example 111
1-(2-Isopropoxyethyl)-5-(N-isopropyl-N-methylamino)-7-(4-methLrlpyridin-2-
ylamino)-
1 H-pyrazolo f4,3-dlpyrimidine-3-carboxylic acid
CH3
N-
H3C O N

N~ / ~ N CH3
HO N- CH3
~
N
O H3C CH3
The ester of preparation 106 (140mg, 0.32mmol) was dissolved in methanol (2mL)
and the solution treated with I M aqueous sodium hydroxide solution (640 L).
The
reaction mixture was stirred at room temperature for 18 hours before being
concentrated in vacuo. The residue was dissolved in water (20mL), washed with
ethyl acetate (10mL), acidified with citric acid and extracted with
dichloromethane
(2x2OmL). The organics were combined, dried over magnesium sulphate and
concentrated in vacuo: The residue was purified by column chromatography on
silica
gel eluting with dichloromethane:methanol 100:0 to 95:5. The product was
triturated
with ether to yield the title product as a white solid, 45mg.

'H NMR (CD3OD, 400MHz) 8: 1.10 (d, 6H), 1.32 (d, 6H), 2.42 (s, 3H), 3.12 (s,
3H),
3.66 (m, 1 H), 3.94 (t, 2H), 4.83 (t, 2H), 5.05 (m, 1 H), 7.04 (d, 1 H), 8.16
(s, 1 H), 8.20
(d, 1 H). MS ES+ m/z 428 [MH]+


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Example 112
(2'R)-5-(N-isopropyl-N-methylamino)-1-(2'-methoxyprop rl -7-(4-methYlpyridin-2-

lamino)-1 H-pyrazolo[4 3-d]pyrimidine-3-carboxylic acid
O~CH3
H3C
-1) N
N
N~ I N CH3
CH3
HO N ~
O H C CH3
3
The title compound was prepared by a method similar to that described for
example 111 using the ester of preparation 105.

'H NMR (CD3OD, 400MHz) 5: 1.32 (m, 9H), 2.44 (s, 3H), 3.10 (s, 3H), 3.42 (s,
3H),
3.97 (m, 1 H), 4.73 (m, 2H), 4.99 (m, 1 H), 7.08 (m, 1 H), 8.08 (s, 1 H), 8.20
(d, 1 H).
MS APCI+ m/z 414 [MH]+
Example 113
N-[1-(2-EthoxyethrLl)-5-(N-isopropyl-N-methylamino)-7-(4-methylpyridin-2-
ylamino)-
1 H-pyrazolo[4,3-dlpyrimidine-3-carbony1lmethanesulfonamide

H3CO N \

N/IN N CH3
H ~ CH3
N N N --/\
H S\\O O H C CH3
H3C 3

The chloro compound of preparation 186 (90mg, 0.20mmol), N-methyl-

isopropylamine (73mg, 1.Ommol), N-ethyldiisopropylamine (170 L, 1.Ommol) and
caesium fluoride (30mg, 0.20mmol) were dissolved in dimethyl sulphoxide (1 mL)
and the reaction mixture stirred at 110 C for 5 hours. The reaction mixture
was
allowed to cool and was then diluted with ethyl acetate (10mL) and water
(10mL).
The organic phase was separated and washed with water (2x10mL), dried over


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magnesium sulphate and concentrated in vacuo. The residue was purified twice
by
column chromatography on silica gel eluting with dichloromethane:methanol 99:1
to
97:3. The crude product was dissolved in ethyl acetate (2mL) and treated with
pentane. The precipitate formed was filtered off and dried in vacuo to yield
the title
product, 42mg.

'H NMR (DMSO-D6 + CF3CO2D, 400MHz) b: 0.98 (t, 3H), 1.18 (d, 6H), 2.44 (s,
3H),
3.02 (s, 3H), 3.40 (s, 3H), 3.44 (d, 2H), 3.86 (t, 2H), 4.75 (m, 1 H), 4.94
(t, 2H), 7.18
(d, 1 H), 8.06 (s, 1 H), 8.25 (d, 1 H). MS ES- m/z 489 [M-H]-

Example 114
N-[5-(Dimethylamino)-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-
pyrazolo[4,3-dlpyrimidine-3-carbonyl]methanesulfonamide

H3C~0 N
N
N~ ~ CH
N 3
N N -CH
S N s
H3C O O H3C

The title product was prepared by a method similar to that described for
example
113 using a 33% solution of dimethylamine in ethanol as the source of the
HNR3R4
amine. 55mg of the desired product was produced.

'H NMR (DMSO-D6 + CF3CO2D, 400MHz) & 0.97 (t, 3H), 2.45 (s, 3H), 3.20 (s, 6H),
3.40 (s, 3H), 3.44 (d, 2H), 3.88 (t, 2H), 4.95 (t, 2H), 7.18 (d, 1 H), 8.07
(s, 1 H), 8.25
(d, 1 H), 13.40 (s, 1 H). MS ES+ m/z 485 [MNa]+



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Example 115
N-[1-(2-Ethoxyethyl)-5-(N-ethyl-N-methylamino)-7-(4-methylpyridin-2-ylamino)-1
H-
pyrazolo[4,3-d]pyrimidine-3-carbonyl]methanesulfonamide
H3C0 N

N CH3
0\\ N N N

H C S\\O 0 H C~CH3
3 3

The chloro compound of preparation 186 (110mg, 0.24mmol), N-methyl-ethylamine
(79mg, 1.2mmol), N-ethyldiisopropylamine (210 1, 1.20mmol) and caesium
fluoride
(37mg, 0.24mmol) were dissolved in dimethyl sulphoxide (1 mL) and the reaction
mixture heated to 110 C for 5 hours in a ReactiVialT"'. The reaction mixture
was
partitioned between ethyl acetate (10mL) and water (10mL) and the organic
phase
separated and washed with water (2x10mL). The organic phase was then dried
over
magnesium sulphate and concentrated in vacuo. The residue was purified by
column chromatography on silica gel eluting with dichloromethane:methanol 99:1
to
97:3 to yield the title product as a pale yellow solid, 66mg.
Alternatively, example 115 may be prepared using the carboxylic acid of
Example
96. The carboxylic acid of example 96 (1.0g, 2.50mmol), methanesulphonamide
(356mg, 3.75mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(1.0g, 5.2mmol) and 4-dimethylaminopyridine (305mg, 2.5mmol) were dissolved in
dichloromethane (5mL) and the reaction mixture stirred at room temperature for
16
hours. The reaction mixture was diluted with 10% aqueous citric acid (3mL) and
the
organic phase was separated, washed with water (3mL), dried over magnesium
sulphate and concentrated in vacuo.

'H NMR (DMSO-D6 + CF3COZD, 400MHz) 5: 0.99 (t, 3H), 1.17 (t, 3H), 2.44 (s,
3H),
3.18 (s, 3H), 3.41 (s, 3H), 3.44 (d, 2H), 3.66 (d, 2H), 3.88 (t, 2H), 4.93 (t,
2H), 7.16
(d, 1 H), 8.09 (s, 1 H), 8.26 (d, 1 H). MS ES- m/z 475 [M-H]"

Example 116


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Methyl 1-(2-ethoxyethyl)-5-[ethyl(methyl aminol-7-r(4-fluoro-3-
methylphenyl)aminol
1 H-pyrazolo[4,3-dlpyrimidine-3-carboxylate
CH3
F
0 CH3
HN
N N
N\ I II
N~CH3
N

O 0
H3C
H3C

A mixture of the chloride from preparation 92 (200mg, 0.49mmol), N-
ethylmethylamine (0.084mL, 0.98mmol) and N-ethyldiisopropylamine (0.17mL,
0.98mmol) in dimethylsulphoxide (2mL) was heated in a Reactivial at 120 C for
18
hours. The cooled mixture was concentrated under reduced pressure and the
residue partitioned between dichloromethane (100mL) and water (100mL) and the
layers separated. The aqueous solution was extracted with further
dichloromethane
(50mL) and the combined organic solutions were washed with water (100mL),
brine
(50mL), dried over magnesium sulphate and evaporated under reduced pressure.
The crude product was purified by column chromatography on an Isolute silica
gel
cartridge using dichloromethane:methanol (100:0 to 95:5) as an elution
gradient to
provide, the title compound as a white crystalline solid, 70mg.

'H NMR (CD30D, 400MHz) b: 1.15 (t, 3H), 1.20 (t, 3H), 2.30 (s, 3H), 3.19 (s,
3H),
3.60 (q, 2H), 3.70 (q, 2H), 3.96 (s, 3H), 3.98 (m, 2H), 4.80 (t, 2H), 7.01 (m,
1 H), 7.42
(m, 1 H), 7.67 (m, 1 H).
MS APCI+ m/z431 [MH]+
Example 117
Methyl 5-(diethylamino)-1-(2-ethoxLrethyl)-7-[(4-fluoro-3-methylphenyl)aminol-
1 H-
pyrazolo[4,3-dlpyrimidine-3-carboxylate


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CH3
F
O CH3
HN
jN::] N N

'/ NCH
~ s
O ~ H3C
H3C
The title compound was obtained as a white crystalline solid from the compound
from preparation 92, after re-crystallisation from methanol, following a
similar
procedure to that described in example 116.

'H NMR (CDCI3, 400MHz) 8: 1.20 (m, 9H), 2.30 (s, 3H), 3.65 (m, 6H), 4.00 (m,
5H),
4.75 (t, 2H), 6.95 (m, 1 H), 7.35 (m, 1 H), 7.60 (m, 1 H).
MS APCI+ m/z445 [MH]+
Example 118
1-(2-Ethoxyethyl)-5-[ethyl(methyl)amino]-7-[(3-methylphenyl)amino]-1 H-
pyrazolo[4,3-
dlpyrimidine-3-carboxylic acid

O/--CH3

HN JaCH3
iN N NCH 3
I
O OH CH3

A mixture of the chloride from preparation 238 (200mg, 0.53mmol), cesium
fluoride
(81 mg, 0.53mmol) and N-ethylmethylamine (0.25mL, 2.65mmol) in
dimethylsulphoxide (1.5mL) was heated in a Reactivial at 110 C for 18 hours.
The
cooled mixture was partitioned between dichloromethane (50mL) and I N citric
acid
solution (100mL) and the layers separated. The aqueous solution was extracted
with
further dichloromethane (50mL) and the combined organic solutions washed with
water (2x100mL) and then brine (50mL). The solution was dried over magnesium


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sulphate and concentrated under reduced pressure to provide the title compound
as
a white solid, 150mg.

'H NMR (400 MHz, CD3OD) 8: 1.10 (t, 3H), 1.25 (t, 3H), 2.40 (s, 3H), 3.25 (s,
3H),
3.65 (q, 2H), 3.75 (q, 2H), 4.00 (t, 2H); 4.85 (t, 2H), 7.10 (d, 1 H), 7.35
(m, 1 H), 7.50
(d, 1 H), 7.61 (s, 1 H).
MS APCI+ mlz 399 [MH]+
Examples 119 to 124

The following compounds of the general formula shown below:
1
R6 HN'R
N N N
N,Rs
N i
O OH Ra

were prepared from the corresponding chloride compounds from preparations 149,
231, 232 and 237, following a similar procedure to that described in example
118.
1
HN
R\
\
N N
N~
N ' 'N~CHs
~
O OH CHs
Ex HNR1, R6 Yield/Data

H3C' C i a~" Yellow crystals (93%)
~1H CH1H NMR (DMSO-D6+drop TFA-d,
3 400MHz) S: 1.14 (t, 3H), 2.45 (s, 3H),
119 3.20 (s, 6H), 3.63 (q, 2H), 3.81 (t, 2H),
4.98 (t, 2H), 7.16 (d, 1 H), 8.11 (s, 1 H),
8.24 (d, 1 H).
MS m/z 386 [MH]+


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H3C^o Yellow solid (85%)
'H NMR (DMSO-D6+drop TFA-d,

N^N 400MHz) S: 1.02 (t, 3H), 1.19 (t, 3H), 2.57
120 NH' ~CH3 (s, 3H), 3.19 (s, 3H), 3.48 (q, 2H), 3.68
(q, 2H), 3.83 (t, 2H), 4.82 (t, 2H), 8.08 (s,
1 H), 9.02 (s, 1 H).
MS m/z 401 [MH]+
H3C^0 Yellow oil, (88%)
~H / CH 'H NMR (DMSO-D6, 400MHz) 8: 0.95 (t,
3H), 1.15 (t, 3H), 3.17 (s, 3H), 3.39 (q,
121 2H), 3.66 (q, 2H), 3.83 (t, 2H), 4.63 (s,
2H), 4.95 (t, 2H), 7.14 (d, 1 H), 8.19 (d,
1 H), 8.34 (s, 1 H).
MS m/z 416 [MH]+
CH3 Yellow powder (50%)

p 'H NMR (CD3OD, 400MHz) 8: 1.30 (t,
I, 3H), 1.50 (m, 1 H), 1.60 (m, 1 H), 1.90 (m,
122" 'NH N 2H), 2.12 (m, 2H), 2.45 (s, 3H), 3.30 (s,
3H), 3.80 (q, 2H), 3.90 (t, 2H), 4.00 (m,
1 H), 4.90 (m, 2H), 7.05 (d, I H), 8.20 (m,
2H).

1
HN,R
R\
\
N I N CH3
N \
/
N N ""~ CH3
0 0 H CH3


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H3C^ N^N Yellow solid (69%)

!'NH I ~ CH 'H NMR (DMSO-D6+drop TFA-d,
3
400MHz) 6: 1.02 (t, 3H), 1.21 (d, 6H),
123 2.57 (s, 3H), 3.02 (s, 3H), 3.48 (q, 2H),
3.82 (t, 2H), 4.82 (t, 2H), 4.95 (m, I H),
8.04 (s, 1 H), 9.03 (s, 1 H).
MS m/z 415 [MH]+

CH3 Pale yellow powder (45%)

p 'H NMR (CD3OD, 400MHz) 6: 1.35 (d,
I, 6H), 1.45 (m, 1 H), 1.60 (m, 1 H), 1.90 (m,
124 " 'NH N 2H), 2.10 (m, 2H), 2.45 (s, 3H), 3.15 (s,
3H), 3.30 (m, 1 H), 3.90 (t, 2H), 4.05 (m,
1 H), 5.02 (m, 2H), 7.05 (d, 1 H), 8.20 (m,
2H).
MS APCI+ m/z 440 [MH]+

A-The product was recrystallised from dichloromethane, then sonicated in ether
and
dried in vacuo.
Example 125

5-(Diethylamino)-1-(2-ethoxyethyl)-7-f(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)aminol-1 H-
pyrazolof4,3-dlpyrimidine-3-carboxylic acid

O CH3

HN CN~OCH3
N N
N~ I
' N~CH
N ~ 3
O OH CH3

A mixture of the chloro compound from preparation 239 (170mg, 0.43mmol),
diethylamine (0.18mL, 1.73mmol) and cesium fluoride (66mg, 0.43mmol) in

dimethylsulphoxide (1 mL) was stirred at 110 C for 2 hours. Additional
diethylamine


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(0.18mL, 1.73mmol) in dimethylsulphoxide (0.5mL) was added, the mixture
transferred to a Reactivial and stirred at 110 C for a further 2 hours. The
cooled
mixture was diluted with dichloromethane (40mL) and washed with 1 M citric
acid
solution (3x2OmL). The combined aqueous solutions were washed with
dichloromethane (20mL), then basified to pH 6 using solid sodium bicarbonate.
This
solution was extracted with dichloromethane (3x3OmL) and the combined organic
solutions washed with water (20mL) and brine (20mL) then dried (using a phase
separation cartridge) and concentrated under reduced pressure. The resulting
oil
was suspended in water (30mL) and the mixture sonicated for 30 minutes. The
resulting solid was filtered off and dried in vacuo to provide the title
compound as a
solid.
'H NMR (CD3OD, 400MHz) b: 1.12 (t, 3H), 1.25 (t, 6H), 3.59 (q, 2H), 3.62 (s,
3H),
3.65 (m, 4H), 3.92 (t, 2H), 4.90 (m, 2H), 6.65 (d, 1 H), 7.75 (m, 1 H), 8.10
(s, 1 H).
MS ES- m/z 428 [M-H]-
Example 126
5-[Isopropyl(methyI)amino]-7-[(4-methypyridin-2-yl)amino]-1-[2-(2,2,2-
trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-3-carbox li
CH3
O CE3
HN N
N I N CH3
N \
N NCH3
I
O OH CH3

A mixture of the chloride from preparation 233 (75mg, 0.17mmol), N-
ethyldiisopropylamine (0.15mL, 0.85mmol), cesium fluoride (26mg, 0.17mmol) and
N-methylisopropylamine (0.09mL, 0.85mmol) in 1-methyl-2-pyrrolidinone (1mL)
was
stirred at 110 C in a Reactivial for 4 hours.
The cooled reaction mixture was purified directly using a Phenomenex Luna C18
reverse phase silica gel column and acetonitrile:95% water/5% methanol/0.1 %


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trifluoroacetic acid (5:95 to 95:5) as elution gradient. The product was
dissolved in
dichloromethane and the solution washed with sodium bicarbonate solution,
dried
over magnesium sulphate and evaporated under reduced pressure to provide the
title compound, 24mg.

5'H NMR (CD3OD, 400MHz) S: 1.31 (d, 6H), 2.48 (s, 3H), 3.11 (s, 3H), 3.98 (q,
2H),
4.15 (t, 2H), 4.95 (m, 1 H), 4.99 (t, 2H), 7.08 (d, 1 H), 8.00 (s, 1 H), 8.12
(d, 1 H).
MS ES- m/z 466 [M-H]-
Example 127
5-[Ethyl(methyl)amino]-7-[(4-methYlpyridin-2-yl)amino]-1-[2-(2,2,2-
trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid
CH3

O CF3

HN N
N N
N ~
' NCH
N 3
O OH CH3

The title compound was prepared from the compound from preparation 233 and N-
ethylmethylamine, following a similar procedure to that described in example
126,
except only 2 equivalents of N-ethylmethylamine and N-ethyldiisopropylamine
were
used.

'H NMR (CD3OD, 400MHz) 8: 1.30 (t, 3H), 2.49 (s, 3H), 3.26 (s, 3H), 3.73 (q,
2H),
3.98 (q, 2H), 4.16 (t, 2H), 4.98 (t, 2H), 7.05 (d, 1 H), 8.00 (s, 1 H), 8.10
(d, 1 H).

MS ES- m/z 452 [M-H]-
Example 128


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5-(Diethylamino)-7-[(4-methylpyridin-2-yl)aminol-l-f2-(2,2,2-
trifluoroethoxy)ethyll-1 H-
pyrazolor4,3-d1pYrimidine-3-carboxylic acid
CH3
O CF3
HN N
N N
N\ I ~

N NCH3
O OH CH3

A mixture of the chloride from preparation 233 (100mg, 0.23mmol), cesium
fluoride
(35mg, 0.23mmol) and diethylamine (0.07mL, 0.69mmol) in dimethylsulphoxide

(1 mL) was stirred at 120 C in a Reactivial for 18 hours.
Tlc analysis showed starting material remaining, so additional diethylamine
(0.07mL,
0.69mmol) was added and the reaction heated for a further 3 hours at 135 C.
The
cooled mixture was suspended in 1 M citric acid solution (200mL) and extracted
with
dichloromethane (3x5OmL). The combined organic extracts were washed with water
(50mL), brine (25mL) and dried over sodium sulphate then concentrated under
reduced pressure. The crude product was purified by column chromatography
using
a silica gel Isolute cartridge and an elution gradient of 10% acetic acid in
methanol:dichloromethane: (1:99 to 7:93). The product was triturated with
ether and
dried in vacuo to afford the title compound as a yellow powder, 44mg.

'H NMR (CD3OD, 400MHz) 8: 1.35 (t, 6H), 2.50 (s, 3H), 3.70 (q, 4H), 4.00 (q,
2H),
4.18 (t, 2H), 5.00 (t, 2H), 7.10 (d, 1 H), 8.05 (s, 1 H), 8.13 (d, 1 H).

MS ES+m/z 468 [MH]+
Example 129


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7-[(4-Methypyridin-2-yl)aminol-5-(2-methylpyrrolidin-1-yl)-1-[2-(2,2,2-
trifluoroethoxy)ethyl]-1 H-pyrazolof4 3-dlpyrimidine-3-carbox liy c acid
CH3
o CF3

HN N
NN N CH3
N
N ~6
O OH

The title compound was obtained as a solid in 45% yield from 2-
methylpyrrolidine
and the chloride from preparation 233, following the procedure described in
example
128.
'H NMR (CD3OD, 400MHz) 8: 1.38 (d, 3H), 1.85 (m, 1 H), 2.10 (m, 1 H), 2.25 (m,
2H),
2.50 (s, 3H), 3.60 (m, 1 H), 3.79 (m, 1 H), 3.98 (q, 2H), 4.15 (t, 2H), 4.45
(m, 1 H), 5.00
(t, 2H), 7.10 (d, 1 H), 7.98 (s, 1 H), 8.15 (d, 1 H).
MS ES+ m/z480 [MH]+
Example 130
5-[Cyclobutyl(methyl)aminol-7-[(4-methylpyridin-2-Zl amino]-1-[2-(2,2,2-
trifluoroethoxy)eth ly1-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxylic acid
CH3
O/"--CF3

HN N
N N
N ~ C N N

O OH 6

The title compound was obtained in 42% yield as a yellow solid, from the amine
from
preparation 241 and the chloro compound from preparation 233, following a
similar


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procedure to that described in example 128, except 5eq N-ethyldiisopropylamine
was also added.

'H NMR (CD3OD, 400MHz) 8: 1.80 (m, 2H), 2.35 (m, 4H), 2.50 (s, 3H), 3.21 (s,
3H),
3.99 (q, 2H), 4.18 (t, 2H), 4.80 (m, 1 H), 4.99 (t, 2H), 7.10 (d, 1 H), 8.05
(s, 1 H), 8.18
(d, 1 H).
MS APCI+ m/z480 [MH]+
Examples 131 to 133
CH3
0 /--O

HN N
N~
~N, Rs
N OH N
N 1O Ra

A solution of the appropriate esters from preparations 240-242 (0.5mmol) in
sodium
hydroxide (1 N, 4mL, 4mmol) and dioxan (2 mL) was stirred at room temperature
for
18 hours. The solution was concentrated under reduced pressure and the residue
partitioned between dichloromethane (20mL) and 1 M citric acid solution
(10mL). The
layers were separated and the organic phase dried over magnesium sulphate and
evaporated under reduced pressure to give the title compounds.

Ex No -NR3R4 Data

131 *,~,CH3 'H NMR (DMSO-D6 + ldp TFAD), 400MHz) 8: 0.65 (t,
3H), 1.18 (t, 3H), 1.38 (m, 2H), 3.18 (s, 3H), 3.34 (t,
CH3 2H), 3.62 (q, 2H), 3.82 (t, 2H), 4.98 (t, 2H), 7.28 (m,

1 H), 8.20 (m, 2H), 8.38 (d, 1 H).
MS APCI+ m/z400 [MH]+

132 CH3 'H NMR (DMSO-D6+ 1dp TFAD, 400MHz) 8: 0.65 (t,
3H), 1.18 (d, 6H), 1.38 (m, 2H), 3.04 (s, 3H), 3.22 (t, 1~ H3C CH3 2H), 3.84
(t, 2H), 4.70 (m, 1 H), 4.98 (t, 2H), 7.30 (m,

1 H), 8.20 (m, 2H), 8.40 (d, 1 H).
MS APCI+ m/z414 [MH]+


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133 *"NCH 'H NMR (DMSO-D6+ 1dp TFAD, 400MHz) 8: 0.66 (t,
3H), 1.20 (t, 6H), 1.39 (m, 2H), 3.30 (t, 2H), 3.62 (q,
CH3 4H), 3.84 (t, 2H), 4.98 (t, 2H), 7.28 (m, 1 H), 8.20 (m,
2H), 8.38 (d, 1 H).
MS APCI+ m/z414 [MH]+
Example 134
1-(2-Ethoxyethyl -7-[(4-methylpyridin-2-yl)aminol-5-pyrrolidin-lyl-1 H-
pyrazolo[4,3-
dlpyrimidine-3-carbox lic acid
CH3
O CH3
HN N
N N
N\ I ~
N N 0
O OH

A solution of the ester from preparation 259 (50mg, 0.12mmol) in 1 N sodium
hydroxide solution (1 mL) and dioxan (0.5mL) was stirred at room temperature
for 18
hours. The mixture was diluted with 1 M citric acid solution (50mL) and
extracted with
dichloromethane (3x200mL). The combined organic extracts were dried over
magnesium sulphate and evaporated under reduced pressure. The crude product
was purified by column chromatography using an Isolute silica gel cartridge
and an
elution gradient of dichloromethane:methanol (100:0 to 90:10) to provide the
title
compound as a yellow solid, 23mg.

'H NMR (CD3OD,400MHz) 8: 1.10 (t, 3H), 2.10 (m, 4H), 2.45 (s, 3H), 3.59 (m,
2H),
3.70 (m, 4H), 3.90 (t, 2H), 4.90 (m, 2H), 7.05 (d, 1 H), 8.20 (m, 2H).
MS APCI+ m/z 412 [MH]+
Example 135
5-[Isopropyl(methyl)aminol-l-f(2S)-2-methoxypropyl]-7-[(4-methylp ridr~ in=2-
yI)aminol-
1 H-pyrazolo[4,3-dlpyrimidine-3-carboxylic acid


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CH3
H3C

HN N H3C
N N
N \ I
~ ~CH3
N N
O OH CH
H3C 3

A solution of the ester from preparation 260 (43mg, 0.1 mmol) in dioxan (2mL)
and
sodium hydroxide (IN, 4mL) was stirred at room temperature for 18 hours. The
mixture was concentrated under reduced pressure and the residue diluted with
citric
acid solution (1 M, 50mL). This solution was extracted with dichloromethane
(3x5OmL), the combined organic solutions washed with sodium bicarbonate
solution
(3x15mL), dried over magnesium sulphate and evaporated under reduced pressure.
The crude product was purified by column chromatography using an Isolute
silica
gel cartridge and an elution gradient of dichloromethane:methanol (100:0 to
94:6) to
give a yellow oil. This was triturated with ether and the resulting solid
filtered off and
dried to give the title compound as a white solid, 26mg.

'H NMR (CD3OD,400MHz) S: 1.30 (m, 9H), 2.42 (s, 3H), 3.10 (s, 3H), 3.43 (s,
3H),
4.00 (m, 1 H), 4.75 (m, 2H), 4.99 (m, 1 H), 7.02 (d, 1 H), 8.08 (s, 1 H), 8.10
(d, 1 H).
MS APCI+ m/z 414 [MH]+

Examples 136 to 140
CH~R7c
/CF3 HN NN OH N

\ R3
N N
O Ra


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A solution of the appropriate esters from preparations 245-249 (1 eq) in
sodium
hydroxide (1 N, 1.5-3eq) and dioxan (6.5-7.5 mLmmol-') was stirred at room
temperature for 18 hours. The solution was concentrated under reduced pressure
and the residue partitioned between dichloromethane and 1 M citric acid
solution and
the layers separated. The aqueous phase was extracted with additional
dichloromethane, the combined organic solutions dried over magnesium sulphate
and evaporated under reduced pressure. The products were triturated with ethyl
acetate, and the solids filtered and dried to afford the title compounds as
white
crystalline solids.

Ex No -NR3R`` R' Data

136 ,CH3 H 'H NMR (CD3OD, 400MHz) 8: 1.20 (t, 3H),
2.38 (s, 3H), 3.24 (s, 3H), 3.57 (q, 2H), 4.02
CH3 (q, 2H), 4.15 (t, 2H), 4.94 (t, 2H), 7.10 (d,

1 H), 7.32 (m, 1 H), 7.40 (d, 1 H), 7.50 (s, 1 H).
MS APCI+ m/z453 [MH]+

137 N~.,V~CH3 F 'H NMR (CD3OD, 400MHz) b: 1.08 (t, 3H),
2.30 (s, 3H), 3.22 (s, 3H), 3.64 (q, 2H), 4.00
CH3 (q, 2H), 4.10 (t, 2H), 4.94 (t, 2H), 7.10 (d,

1 H), 7.40 (m, 1 H), 7.50 (s, 1 H).
MS APCI+ m/z471 [MH]+

138 lw,~,,CH3 H 'H NMR (CD3OD, 400MHz) S: 1.22 (d, 6H),
2.40 (s, 3H), 3.08 (s, 3H), 4.04 (q, 2H), 4.13
H3C CH3 (t, 2H), 4.85 (m, 1 H), 4.94 (t, 2H), 7.12 (d,

1 H), 7.32 (m, 1 H), 7.39 (d, 1 H), 7.50 (s, 1 H).
MS APCI+ m/z467 [MH]+

139 N~,,NCH3 F 'H NMR (CD3OD, 400MHz) 8: 1.22 (d, 6H),
2.30 (s, 3H), 3.08 (s, 3H), 4.00 (q, 2H), 4.12
H3C CH3 (t, 2H), 4.80 (m, 1 H), 4.94 (t, 2H), 7.10 (m,

1 H), 7.37 (m, 1 H), 7.49 (m, 1 H).
MS APCI+ m/z 485 [MH]+


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140 '-N--"~CH F 'H NMR (CD3OD, 400MHz) 8: 1.24 (t, 6H),
3 2.31 (s, 3H), 3.62 (q, 4H), 4.02 (q, 2H),
CH3 4.15 (t, 2H), 4.86 (t, 2H), 7.10 (m, 1 H), 7.37
(m, 1 H), 7.52 (m, 1 H).
MS APCI+ m/z 485 [MH]+
Examples 141 to 146
Sodium hydroxide solution (1 M, 3eq) was added to a solution of the esters
from
preparations 253-258 (1 eq) in dioxane (8.5-10.5mLmmol-1), and the reaction
mixture
stirred at room temperature for 18 hours. The solvent was removed under
reduced
pressure and the residue partitioned between citric acid (15mL) and
dichloromethane (15mL). The phases were separated and the organic layer
evaporated under reduced pressure to provide the title compounds.

F F O N F HN CH3
a
N~ /R3
N OH N
N N
O Ra
Ex. No Yield(%) Data

141 '*~,CH3 96 MS APCI+ m/z 468 [MH]+
CH3

142 ,CH3 89 MS APCI+ m/z 482 [MH]+
H CCH
3 3

143 '--NCH 99 MS APCI+ m/z 482 [MH]+
CH3


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~
F

HNNI
~ CH3
N\ R3
N OH N
N%N 4
O R

144 ~.,CH3 99 MS APCI+ m/z 432 [MH]+
CH3

145 '*~CH3 90 MS APCI+ m/z 446 [MH]+
H3C CH3

146 '---N^CH3 95 MS APCI+ m/z 446 [MH]+
CH3

Example 147
2-(Dimethylamino)ethyl 1-(2-ethoxyethyl)-5-[isopropyl(methyl)amino]-7-[(4-
methylp ridy in-2-yl)amino]-1 H-pyrazolo[4,3-dlpyrimidine-3-carboxylate


06CH3 N a
HN CH3
iN I N CH3
~
i `N CH
N 1 3
O O CH3
H3C~-N\ CH
3
3


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A mixture of the chloride from preparation 176 (160mg, 0.36mmol), cesium
fluoride
(54mg, 0.36mmol) and N-methylisopropylamine (186 L, 1.79mmol) in
dimethylsulphoxide (3mL) was heated at 110 C in a Reactivial for 18 hours.
The
cooled mixture was partitioned between dichloromethane (20mL) and water (20mL)
and the layers separated. The aqueous solution was extracted further with
dichloromethane (20mL) and the combined organic solutions washed with water
(3x2OmL), dried over magnesium sulphate and evaporated under reduced pressure.
The residual orange oil was purified by column chromatography using an Isolute

silica gel cartridge and an elution gradient of methanol:dichloromethane
(0:100 to
10:90), and then on reverse phase silica gel using acetonitrile:water
:trifluoroacetic
acid (95:5:0.1) as eluant to provide the title compound, 15mg.

'H NMR (CD3OD, 400MHz) S: 1.09 (t, 3H), 1.33 (d, 6H), 2.54 (s, 3H), 3.05 (s,
6H),
3.16 (s, 3H), 3.51 (q, 2H), 3.65 (t, 2H), 3.98 (t, 2H), 4.78 (t, 2H), 4.89 (m,
1 H), 5.04
(t, 2H), 7.18 (d, 1 H), 8.08 (s, 1 H), 8.14 (d, 1 H).
MS m/z 485 [MH]*
Examples 148 to 164
4-Dimethylaminopyridine (1.3 eq) was added to a solution of the appropriate
acid
from examples 11,14,15,17, 38, 96, 118-124, 136, 137 and 139 (1 eq), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3eq) and the
appropriate
sulphonamide (1.2-1.3eq) in dichloromethane (13-30mLmmol"') and the reaction
stirred at room temperature for 18 hours. The mixture was diluted with
dichloromethane, washed with I M citric acid solution, dried over magnesium
sulphate and evaporated under reduced pressure to afford the title compounds.

H3C~0 N

N "I N CH3
H
N N
S ~ 0 N~CH
H3C 0 H3C 3

148A 'H NMR (CDCI3, 400MHz) b: 1.15 (t, 3H), 1.25 (t, 3H), 2.38 (s, 3H),


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3.20 (s, 3H), 3.38 (s, 3H), 3.62 (q, 2H), 3.70 (q, 2H), 3.98 (t, 2H),
4.82 (t, 2H), 7.00 (d, 1 H), 7.25 (m, 1 H), 7.50 (d, 1 H), 7.70 (s, 1 H).
MS APCI+ m/z 476 [MH]+

R7c
H3C~0 N
NiN \ N R7a
N'
O N N_,R3

H3C O R4
149 R3 =-CH2CH3; R4 = -CH3; R'A = CH3; R 7C = H

'H NMR (CDCI3, 400MHz) b: 1.19 (t, 3H), 1.26 (t, 3H), 2.50 (s, 3H),
3.23 (s, 3H), 3.41 (s, 3H), 3.65 (q, 2H), 3.75 (q, 2H), 3.97 (t, 2H),
4.87 (m, 2H), 6.98 (d, 1 H), 7.71 (m, 1 H), 8.18 (br m, 1 H). MS m/z
477 [MH]+
150A R3 =-(CH2)2CH3; R4 = -CH3; R'" = H; R 7C = CH3

'H NMR (DMSO-D6+ drop TFAd, 400MHz) 8: 0.88 (t, 3H), 1.01 (t,
3H), 1.63 (m, 2H), 2.41 (s, 3H), 3.18 (s, 3H), 3.42 (s, 3H), 3.47 (q,
2H), 3.55 (t, 2H), 3.87 (t, 2H), 4.89 (m, 2H), 7.09 (m, 1 H), 8.05 (s,
I H), 8.24 (d, .1 H). MS ESI+ m/z 491 [MH]+

151 A R3 = -CH2CH3; R4 = -CH2CH3; R'" = H; R7 = CH3

'H NMR (DMSO-D6+ drop TFAd, 400MHz) 5: 1.02 (t, 3H), 1.20 (t,
6H), 2.39 (s, 3H), 3.41 (s, 3H), 3.48 (q, 2H), 3.61 (q, 4H), 3.87 (t,
2H), 4.87 (m, 2H), 7.08 (m, 1 H), 8.10 (s, 1 H), 8.24 (d, 1 H). MS ESI+
m/z 491 [MH]+
152" R3 =-(CH2)20CH3; R4 = -CH3; R'" = H; R'C = CH3

'H NMR (DMSO-D6+ drop TFAd, 400MHz) 8: 0.99 (t, 3H), 2.44 (s,
3H), 3.21 (s, 3H), 3.30 (br s, 3H), 3.40 (s, 3H), 3.44 (q, 2H), 3.62
(m, 2H), 3.77 (m, 2H), 3.88 (t, 2H), 4.93 (t, 2H), 7.14 (d, 1 H), 8.06 (s,


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1 H), 8.24 (d, 1 H). MS ESI+ m/z 507 [MH]+
153 R3 =-CH2CH3; R4 =-CH3; R'A = H; R'C = CHaOH

'H NMR (CD3OD+ drop TFAd, 400MHz) 8: 1.10 (t, 3H), 1.30 (t, 3H),
3.28 (s, 3H), 3.40 (s, 3H), 3.56 (q, 2H), 3.79 (q, 2H), 3.99 (q, 2H),
4.78 (s, 2H), 5.06 (m, 2H), 7.24 (d, 1 H), 8.19 (s, 1 H), 8.40 (s, 1 H).
MS ESI- m/z 491 [M-H]-

R7c
~

H3C~0 N ~ ~
NiN N R7a
N
H
O~. ~N N N_ R3
S ~
H3C ~ O 0 R/4
154 R3 =-CH3; R4 =-CH3; R7A = H; R'C = CH3

A, B

'H NMR, (CD3OD, 400MHz) 8: 1.13 (t, 3H), 1.41 (t, 3H), 2.43 (s, 3H),
3.29 (s, 6H), 3.57 (q, 2H), 3.62 (q, 2H), 3.96 (t, 2H), 4.87 (m, 2H),
6.98 (d, 1 H), 8.18 (d, 1 H), 8.36 (s, 1 H). MS m/z 477 [MH]+

155 R3 =-CH2CH3; R4 = -CH3; R'A = H; R 7C = CH3
A,B

'H NMR (CD3OD, 400MHz) 8: 1.14 (t, 3H), 1.29 (t, 3H), 1.41 (t, 3H),
2.43 (s, 3H), 3.25 (s, 3H), 3.57 (q, 2H), 3.63 (q, 2H), 3.78 (q, 2H),
3.97 (t, 2H), 4.87 (m, 2H), 6.99 (d, 1 H), 8.18 (d, 1 H), 8.35 (s, 1 H).
MS m/z 491 [IVIH]+

156 R3 =-CH2CH3; R4 =-CH2CH3; R'A = H; R 7C = CH3
A. C

'H NMR (CD30D, 400MHz) 8: 1.14 (t, 3H), 1.32 (t, 6H), 1.40 (t, 3H),
2.43 (s, 3H), 3.56 (q, 2H), 3.63 (q, 2H), 3.73 (q, 4H), 3.97 (t, 2H),
4.85 (m, 2H), 6.98 (d, 1 H), 8.19 (d, 1 H), 8.34 (s, 1 H). MS m/z 505


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~ [MH]+

CH3

H3C~0 N " ~N
N
N
H
O N N_R3
S
H3C O R4
157 R3 = -CH2CH3; R4 = -CH3

'H NMR (CD3OD, 400MHz) S: 1.21 (t, 3H), 1.30 (t, 3H), 2.54 (s, 3H),
3.27 (s, 3H), 3.43 (s, 3H), 3.67 (q, 2H), 3.79 (q, 2H), 3.98 (t, 2H),
4.84 (t, 2H), 8.30 (s, 1 H), 8.71 (s, 1 H). MS m/z 478 [MH]+

158 R3 = -CH2CH3; R4 = -CH2CH3

'H NMR (CD3OD, 400MHz) 5: 1.21 (t, 3H), 1.33 (t, 6H), 2.54 (s, 3H),
3.43 (s, 3H), 3.67 (q, 2H), 3.75 (q, 4H), 3.98 (t, 2H), 4.86 (t, 2H),
8.31 (s, 1 H), 8.72 (s, 1 H). MS m/z 492 [MH]+

R7b
CF3O
R7o
N

N~ N
H
O`\ N N N_R3
S\
H3C 0 O R4
159 R3 =-CH2CH3; R4 =-CH3; R'B =-CH3; R'C = F

'H NMR (CDCI3, 400MHz) 8: 1.18 (m, 3H), 2.30 (s, 3H), 3.17 (s, 3H),
3.43 (s, 3H), 3.66 (q, 2H), 3.93 (q, 2H), 4.26 (q, 2H), 4.80 (q, 2H),
7.00 (dd, I H), 7.36 (br s, I H), 8.05 (s, I H). MS APCI+ m/z 548 [MH]+

160 R3 =-CH2CH3; R4 =-CH2CH3; R'B = -CH3; R 7C = F


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'H NMR (CDCI3, 400MHz) S: 1.20 (m, 6H), 2.28 (s, 3H), 3.42 (s, 3H),
3.60 (q, 4H), 3.94 (q, 2H), 4.25 (t, 2H), 4.81 (t, 2H), 7.00 (dd, 1 H),
7.30 (m, 1 H), 7.50 (m, 1 H), 8.06 (br s, 1 H). MS APCI+ m/z 562 [MH]+

161 R3 = -CH2CH3; R4 = -CH3; R'B = -CH3; R'c = H

'H NMR (CDCI3, 400MHz) 8: 1.20 (t, 3H), 2.38 (s, 3H), 3.17 (s, 3H),
3.44 (s, 3H), 3.67 (q, 2H), 3.95 (q, 2H), 4.26 (t, 2H), 4.82 (t, 2H), 6.95
(d, 1 H), 7.26 (m, 1 H), 7.40 (m, 1 H), 7.50 (s, 1 H), 8.18 (s, 1 H). MS
APCI+ m/z 530 [MH]+

R N --
/
6 H
I N~
N N CH3
H
011 N N~ R3
N~
H C S0 0 R4
3
162 R6 = -(CH2)20CH3; R3= -CH2CH3, R4 = -CH3
'H NMR (CD3OD, 400MHz) S: 1.31 (t, 3H), 2.54 (s, 3H), 3.30 (s, 3H),
3.37 (s, 3H), 3.41 (s, 3H), 3.77 (q, 2H), 3.94 (t, 2H), 5.07 (t, 2H), 7.19
(d, 1 H), 8.06 (s, 1 H), 8.14 (d, 1 H). MS m/z 463 [MH]+
163A'E

R6 = 0~\~ ; R3= -CH2CH3, R4 = -CH3

'H NMR (CD30D, 400MHz) 8: 1.30 (t, 3H), 1.45 (m, 1 H), 1.60 (m,
1 H), 1.90 (m, 2H), 2.10 (m, 2H), 2.41 (s, 3H), 3.25 (s, 3H), 3.42 (s,
3H), 3.75 (q, 2H), 3.90 (t, 2H), 4.00 (m, 1 H), 4.85 (m, 2H), 7.00 (d,
1 H), 8.20 (m, 1 H), 8.35 (m, 1 H). MS APCI+ m/z 503 [MH]+

164

A, E
R6 = 0~~ ; R3= -CH(CH3)2; R4 = -CH3

'H NMR (CD3OD, 400MHz) 8: 1.30 (d, 6H), 1.50 (m, I H), 1.62 (m,
1 H), 1.90 (m, 2H), 2.10 (m, 2H), 2.40 (s, 3H), 3.10 (s, 3H), 3.40 (s,


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3H), 3.85 (t, 2H), 4.00 (m, I H), 4.85 (m, 2H), 5.05 (m, 1 H), 6.99 (d,
~
I H), 8.20 (m, I H), 8.30 (m, 1 H). MS APCI+ m/z 517 [MH]+

A-crude compounds were purified by column chromatography on an Isolute silica
gel cartridge using dichloromethane:methanol as eluant.
B-an additional 0.5eq of sulphonamide and 4-dimethylaminopyridine were added
after 18 hours, and the reaction stirred for a further 6 hours.
C-1.5 eq of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-
dimethylaminopyridine and ethylsulphonamide were used.
D-the compound was isolated after trituration with methanol.
E-4-dimethylaminopyridine (0.5eq), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide
hydrochloride (2eq) and the appropriate sulphonamide (2eq) were used.
Examples 165 to 171
4-Dimethylaminopyridine (1.3 eq) was added to a solution of the appropriate
acid
from examples 20 and 131-133 (1 eq), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (1.3eq) and the appropriate sulphonamide (1.2-
1.3eq) in dichloromethane (13-30mLmmol-1) and the reaction stirred at room
temperature for 18 hours. The mixture was washed with 1 M citric acid solution
(5mL), the organic phase separated and purified directly by column
chromatography
on silica gel using an elution gradient of dichloromethane:methanol (100:0 to
95:5)
to afford the title compounds as yellow solids.

~
H3C~\C~ ~ ~
N N

\ N
H
0\ / N N N_R3
R17 S\\O Q R"

165 R3 = -CH3; R4 = -CH2CH3; R" = -CH3;
'H NMR (CDC13, 400MHz) S: 0.75 (t, 3H), 1.24 (t, 3H), 1.60 (m, 2H),
3.24 (s, 3H), 3.42 (s, 3H), 3.56 (t, 2H), 3.75 (q, 2H), 3.98 (t, 2H), 4.84
(m, 2H), 7.04 (m, 1 H), 7.75 (m, 1 H), 8.35 (m, 2H).


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MS APCI+ m/z 477 [MH]+

166 R3 = -CH3; R4 = -CH2CH3; R" = -CH2CH3;

'H NMR (CDCI3, 400MHz) 8: 0.75 (t, 3H), 1.24 (t, 3H), 1.42 (t, 3H),
1.60 (m, 2H), 3.22 (s, 3H), 3.56 (t, 2H), 3.60 (q, 2H), 3.75 (q, 2H), 3.97
(t, 2H), 4.82 (m, 2H), 7.04 (m, 1 H), 7.78 (m, 1 H), 8.40 (m, 2H).
MS APCI+ m/z 491 [MH]+

167 R3 = -CH3; R4 = -CH(CH3)2; R" = -CH3;
'H NMR (CDCI3, 400MHz) 8: 0.75 (t, 3H), 1.24 (d, 6H), 1.58 (m, 2H),
3.06 (s, 3H), 3.44 (s, 3H), 3.50 (m, 2H), 3.98 (t, 2H), 4.84 (m, 2H),
4.95 (m, 1 H), 7.04 (m, 1 H), 7.80 (m, 1 H), 8.35 (m, 2H).
MS APCI+ m/z 491 [MH]+

168 R3 = -CH3; R4 = -CH(CH3)2; R" = -CH2CH3;

'H NMR (CDCI3, 400MHz) 6: 0.73 (t, 3H), 1.24 (d, 6H), 1.42 (t, 3H),
1.56 (m, 2H), 3.04 (s, 3H), 3.55 (m, 2H), 3.60 (q, 2H), 3.98 (t, 2H),
4.82 (m, 2H), 4.95 (m, 1 H), 7.04 (m, 1 H), 7.80 (m, 1 H), 8.35 (d, 1 H),
8.40 (m, 1 H). MS APCI+ m/z 505 [MH]+

169 R3 = -CH2CH3; R4 = -CH2CH3; R" = -CH3;
'H NMR (CDCI3, 400MHz) 5: 0.75 (t, 3H), 1.26 (t, 6H), 1.60 (m, 2H),
3.42 (s, 3H), 3.55 (t, 2H), 3.66 (m, 4H), 3.97 (t, 2H), 4.87 (m, 2H), 7.06
(m, 1 H), 7.78 (m, 1 H), 8.36 (m, 1 H), 8.44 (m, 1 H).
MS APCI+ m/z 491 [MH]+

170 R3 = -CH2CH3; R4 = -CH2CH3; R" = -CH2CH3;

'H NMR (CDCI3, 400MHz) 5: 0.75 (t, 3H), 1.24 (t, 6H), 1.42 (t, 3H),
1.60 (m, 2H), 3.52 (t, 2H), 3.60 (q, 2H), 3.65 (m, 4H), 3.98 (t, 2H),
4.84 (m, 2H), 7.06 (m, 1 H), 7.75 (m, 1 H), 8.34 (m, 1 H), 8.42 (m, 1 H).
MS APCI+ m/z 505 [MH]+


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CH3

H3CO N
~N N
N\ N
H
ON N~ N_ R3
H C 0 R
3
171 R3 = -CH3; R4 = -CH2CH3;
'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 0.64 (t, 3H), 1.16 (t, 3H), 1.35
(m, 2H), 2.45 (s, 3H), 3.15 (s, 3H), 3.32 (t, 2H), 3.40 (s, 3H), 3.64 (q,
2H), 3.86 (t, 2H), 4.94 (m, 2H), 7.18 (d, 1 H), 8.04 (s, 1 H), 8.25 (d, 1 H).
MS APCI+ m/z 491 [MH]+

Examples 172 to 177
4-Dimethylaminopyridine (1.3 eq) was added to a solution of the appropriate
acid
from examples 140-145 (1eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (1.3eq) and methanesulphonamide (1.3eq) in dichloromethane (13.5-

16mLmmol-1) and the reaction stirred at room temperature for 18 hours. TIc
analysis
showed starting material remaining, so additional 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (0.5eq) and methanesulphonamide (0.5eq) were
added and the reaction stirred for a further 18 hours. The mixture was diluted
with
dichloromethane and 1 M citric acid solution, stirring continued for a further
40
minutes, then the phases separated. The organic phase was purified directly by
column chromatography on silica gel (using a Parallel Flashmaster system)
using an
elution gradient of inethanol:dichloromethane (0:100 to 5:95) to provide the
title
compounds as yellow solids.


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~
F
F
F HNN~
\ CH3
N~ Rs
N NH ~N
N N
O Ra
0=5~0
H3C

Ex. No -NR3R4 Data

172 CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) S: 1.17 (t, 3H),
2.35-2.46 (m, 5H), 3.18 (s, 3H), 3.39 (s, 3H), 3.60-
CH3 3.67 (m, 4H), 3.94 (t, 2H), 4.98 (t, 2H), 7.18 (d, 1 H),
8.08 (s, 1 H), 8.26 (d, 1 H).
MS APCI+ m/z 545 [MH]+

173 **,~,,CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 1.19 (d, 6H),
2.40-2.50 (m, 5H), 3.02 (s, 3H), 3.40 (s, 3H), 3.63 (t,
H3C CH3 2H), 3.94 (t, 2H), 4.97 (t, 2H), 7.15 (d, 1 H), 8.05 (s,

1 H), 8.24 (d, 1 H).
MS APCI+ m/z 559 [MH]+

174 '--N--'~CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 1.19 (t, 6H),
2.42 (s, 3H), 2.44-2.53 (m, 2H), 3.40 (s, 3H), 3.64
CH3 (m, 6H), 3.93 (t, 2H), 4.94 (t, 2H), 7.15 (d, 1 H), 8.05

(s, 1 H), 8.26 (d, 1 H).
MS APCI+ m/z 559 [MH]+


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i
F

HNNI
~ CH3
N N
N~ I /Rs
N%N
O R4
NH
O=S~O
CH3
175 ~~CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 1.17 (t, 3H),
1.73-1.86 (m, 2H), 2.41 (s, 3H), 3.17 (s, 3H), 3.41 (s,
CH3 3H), 3.51 (t, 2H), 3.65 (q, 2H), 3.90 (t, 2H), 4.24-4.39
(m, 2H), 4.92 (m, 2H), 7.11 (d, 1 H), 8.07 (s, 1 H),
8.24 (d, 1 H).
MS APCI+ m/z 509 [MH]+

176 '*,~,CH3 'H NMR (DMSO-d6 +TFAd, 400MHz) 8: 1.20 (d, 6H),
1:72-1.85 (m, 2H), 2.42 (s, 3H), 3.01 (s, 3H), 3.41 (s,
H3C CH3 3H), 3.50 (t, 2H), 3.90 (t, 2H), 4.24-4.39 (m, 2H),

4.77 (m, 1 H), 4.94 (t, 2H), 7.13 (d, 1 H), 8.05 (s, 1 H),
8.24 -(d, 1 H).
MS APCI+ m/z 523 [MH]+

177 "--NCH 'H NMR (DMSO-ds +TFAd, 400MHz) 8: 1.20 (t, 6H),
I 3
1.73-1.85 (m, 2H), 2.42 (s, 3H), 3.40 (s, 3H), 3.50 (t,
CH3 2H), 3.62 (q, 4H), 3.89 (t, 2H), 4.24-4.39 (m, 2H),
4.92 (t, 2H), 7.14 (d, 1 H), 8.08 (s, 1 H), 8.26 (d, 1 H).
MS APCI+ m/z 523 [MH]+

Example 178
5-[Ethyl(methyl)aminol-7-[(4-methylpyridin-2-yi)amino]-N-(methylsulfonyl)-1-[2-
(2,2,2-
trifluoroethoxY)eth rl1-1 H-pyrazolo[4,3-d]pyrimidine-3-carboxamide


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CF3
N
HN CH3
N N
N~
N ~N~CH3
I
O NH CH3
O/S`O

H3C
A mixture of the chloride from preparation 261 (50mg, 0.1 mmol), N-
ethyldiisopropylamine (0.05mL, 0.3mmol), N-ethylmethylamine (0.026mL, 0.3mmol)
and cesium fluoride (15mg, 0.1 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was
heated
in a Reactivial at 110 C for 90 minutes.
The.cooled reaction mixture was purified directly using a Phenomenex Luna C18
column reverse phase column and acetonitrile:95% water/5% methanol/0.1 %
trifluoroacetic acid (5:95 to 95:5) as elution gradient. The product was
dissolved in
dichloromethane and the solution washed with sodium bicarbonate solution,
dried
over magnesium sulphate and evaporated under reduced pressure to provide the
title compound, 24mg.
Alternatively, example 178 may be prepared by the method of examples 172-177.
4-
Dimethylaminopyridine (22mg, 0.20mmol) was added to a solution of the acid
from
example 127 (70mg, 0.15mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (38mg, 0.20mmol) and methanesulphonamide (19mg, 0.20mmol) in
dichloromethane (2ml) and the reaction stirred at room temperature for 18
hours.
The mixture was diluted with dichloromethane (20mis) and 1 M citric acid
solution
(10mI), then the phases separated. The organic phase was purified directly by
column chromatography on silica gel (using a Parallel Flashmaster system)
using an
elution gradient of methanol:dichloromethane (0:100 to 2:98) to provide the
title
compound as a yellow solid.


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'H NMR (DMSO-D6 +1 drop TFAd, 400MHz) 8: 1.19 (t, 3H), 2.49 (s, 3H), 3.20 (s,
3H), 3.41 (s, 3H), 3.66 (q, 2H), 4.06 (q, 2H), 4.14 (t, 2H), 5.03 (t, 2H),
7.20 (d, 1 H),
8.12 (s, 1 H), 8.27 (d, 1 H).
MS ES- m/z 529 [M-H]-

Example 179
5-[Isopropyl(methyl)amino]-7-[(4-methylpyridin-2-yl)amino]-N-(methylsulfonyl)-
1-[2-
(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-djpyrimidine-3-carboxamide

CF3
i
O N I
HN ~ CH3

iN N CH3 i N CH
N ~ s
O NH CH3
DS`O

H3C
The title compound was obtained from the chloride from preparation 261 and N-
methylisopropylamine, following the procedure descibed in example 178.

'H NMR (DMSO-D6 + 1 drop TFAd, 400MHz) b: 1.20 (d, 6H), 2.49 (s, 3H), 3.03 (s,
3H), 3.41 (s, 3H), 4.08 (q, 2H), 4.15 (t, 2H), 4.78 (m, 1 H), 5.03 (t, 2H),
7.20 (d, 1 H),
8.10 (s, 1 H), 8.26 (d, 1 H).
MS ES- m/z 543 [M-H]-
Examples 180 to 182


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